WO2012162253A2 - Utilisation d'anticorps ou de fragments d'anticorps anti-cgrp ou anti-cgrp-r dans le traitement ou la prévention de formes chroniques et aiguës de la diarrhée - Google Patents

Utilisation d'anticorps ou de fragments d'anticorps anti-cgrp ou anti-cgrp-r dans le traitement ou la prévention de formes chroniques et aiguës de la diarrhée Download PDF

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WO2012162253A2
WO2012162253A2 PCT/US2012/038869 US2012038869W WO2012162253A2 WO 2012162253 A2 WO2012162253 A2 WO 2012162253A2 US 2012038869 W US2012038869 W US 2012038869W WO 2012162253 A2 WO2012162253 A2 WO 2012162253A2
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seq
cgrp
antibody
diarrhea
sequence
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PCT/US2012/038869
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Andrew F. Russo
Eric A. KAISER
Ana RECOBER
Adisa KUBURAS
Ann C. RADDANT
Brian Robert KOVACEVICH
John A. Latham
Jeffrey T.L. Smith
Leon F. Garcia-Martinez
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Alderbio Holdings Llc
The University Of Iowa Research Foundation
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Priority to CA2836799A priority Critical patent/CA2836799C/fr
Priority to EA201301292A priority patent/EA033109B1/ru
Priority to KR1020137033852A priority patent/KR102128628B1/ko
Priority to CN201280035841.5A priority patent/CN103957935B/zh
Priority to NZ618639A priority patent/NZ618639B2/en
Priority to AU2012258976A priority patent/AU2012258976B8/en
Priority to EP12788717.2A priority patent/EP2709662B1/fr
Priority to DK12788717T priority patent/DK2709662T3/da
Application filed by Alderbio Holdings Llc, The University Of Iowa Research Foundation filed Critical Alderbio Holdings Llc
Priority to CN201810154696.1A priority patent/CN108359008B/zh
Priority to BR112013029951-7A priority patent/BR112013029951B1/pt
Priority to JP2014512928A priority patent/JP6189832B2/ja
Priority to MX2013013534A priority patent/MX365813B/es
Priority to SG2013084587A priority patent/SG194974A1/en
Publication of WO2012162253A2 publication Critical patent/WO2012162253A2/fr
Priority to IL229433A priority patent/IL229433B/en
Priority to AU2017239524A priority patent/AU2017239524B2/en
Priority to AU2019202643A priority patent/AU2019202643B2/en

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    • A—HUMAN NECESSITIES
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A—HUMAN NECESSITIES
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    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/26—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against hormones ; against hormone releasing or inhibiting factors
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    • C07—ORGANIC CHEMISTRY
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
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    • C07K2317/00—Immunoglobulins specific features
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    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention pertains to the discovery that polypeptides that bind to CGRP or CGRP receptor and/or other polypeptides which inhibit the CGRP/CGRP receptor interaction such as anti-CGRP or anti-CGRP receptor antibodies and antibody fragments or fragments of CGRP or the CGRP receptor which inhibit the CGRP/CGRP receptor interaction may be used to treat or prevent diarrhea, especially diarrhea associated with conditions or treatments that result in increased levels of CGRP. Exemplary conditions and treatments involving increased CGRP are identified herein.
  • the invention in particular relates to methods of inhibiting, preventing or treating diarrhea and/or maintaining electrolyte balance and fluid levels in the colon of a subject having a condition or treatment associated with elevated CGRP levels that result in diarrhea and/or increased flux of electrolytes and fluids from the colon comprising administering an effective amount of an anti-CGRP antibody or anti-CGRP antibody fragment.
  • Exemplary conditions include by way of example functional bowel disorder and inflammatory bowel diseases, bacterial or viral infections, and more specifically gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, functional abdominal pain syndrome, diverticulosis, and diverticulitis, Crohn's disease, ileitis, collagenous colitis, lymphocytic colitis, ulcerative colitis, cancers or cancer treatments associated with increased CGRP and diarrhea such as chemotherapy, radiation, medullary thyroid carcinoma, and colorectal cancer.
  • the present invention provides methods of screening polypeptides such as anti-CGRP or anti-CGRP receptor antibodies and fragments thereof (including Fab fragments) having binding specificity to human Calcitonin Gene Related Peptide (hereinafter "CGRP") as well as fragments of CGRP or a CGRP receptor in animal models to determine the in vivo effects thereof, especially their ability to antagonize the adverse side effects of CGRP and to treat conditions involving excess CGRP, especially CGRP associated conditions or treatments associated with diarrhea.
  • polypeptides such as anti-CGRP or anti-CGRP receptor antibodies and fragments thereof (including Fab fragments) having binding specificity to human Calcitonin Gene Related Peptide (hereinafter "CGRP") as well as fragments of CGRP or a CGRP receptor in animal models to determine the in vivo effects thereof, especially their ability to antagonize the adverse side effects of CGRP and to treat conditions involving excess CGRP, especially CGRP associated conditions or treatments associated with diarrhea.
  • CGRP
  • the invention also pertains to methods of screening for diseases and disorders associated with increased CGRP, which are associated with diarrhea and specific therapeutic regimens for preventing or treating diseases and disorders that involve CGRP associated diarrhea by administering said antibodies or fragments thereof, alone or in association with other actives.
  • Calcitonin Gene Related Peptide is produced as a multifunctional neuropeptide of 37 amino acids in length.
  • CGRP-alpha and CGRP- beta differ by three amino acids in humans, and are derived from different genes.
  • the CGRP family of peptides includes amylin, adrenomedullin, and calcitonin, although each has distinct receptors and biological activities. Doods, H., Curr. Op. Invest. Drugs, 2(9): 1261-68 (2001).
  • CGRP CGRP receptor
  • RAMP receptor-associated membrane protein
  • Migraines are neurovascular disorder affecting approximately 10% of the adult population in the U.S., and are typically accompanied by intense headaches. Approximately 20-30% of migraine sufferers experience aura, comprising focal neurological phenomena that precede and/or accompany the event. CGRP is believe to play a prominent role in the development of migraines. For example, plasma concentrations of CGRP were identified elevated in jugular venous blood during the headache phase of migraines, to the exclusion of other neuropeptides.
  • triptans which are a family of tryptamine-based drugs, including sumatriptan and rizatriptan. Members of this family have an affinity for multiple serotonin receptors, including 5-HT IB , 5-HT ID , and 5- HT IF . Members of this family of drugs selectively constrict cerebral vessels, but also cause vasoconstrictive effects on coronary vessels. Durham, P.L., New Eng. J. Med., 350 (11): 1073-75 (2004). There is a theoretical risk of coronary spasm in patients with established heart disease following administration, and cardiac events after taking triptans may rarely occur. Noted to be contraindicated for patients with coronary vascular disease.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • the administration of these treatments may occur at the cost of certain negative consequences.
  • NSAIDs have the potential to cause kidney failure, intestinal bleeding, and liver dysfunction.
  • Narcotics have the potential to cause nausea, vomiting, imparled mental functioning, and addiction. Therefore, it is desirable to identify alternative treatments for pain in order to avoid certain of these negative consequences.
  • CGRP is believed to play a role in a multitude of diseases and disorders, including but not limited to migraines, headaches, and pain. Due to the perceived involvement of CGRP in these diseases and disorders, there remains a need in the art for compositions and methods useful for preventing or treating diseases and disorders associated with CGRP, while avoiding adverse side effects. There especially remains a need in the art for compositions or methods that reduce or inhibit diseases or disorders associated with CGRP, such as migraines, headaches, and pain.
  • CGRP intravenous calcitonin gene-related peptide
  • CGRP Upregulation in dorsal root ganglia and ilea mucosa during Clostridium difficile toxin A-induced enteritis in mice that CGRP may play a role in toxin-A mediated diarrhea and that a CGRP antagonist substantially inhibited toxin-A mediated diarrhea and inflammation.
  • Diarrhea is generally classified as a condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and electrolyte imbalances. In 2009 diarrhea was estimated to have caused 1.1 million deaths in people aged 5 and over and 1.5 million deaths in children under the age of 5. Oral rehydration solutions (ORS) with modest amounts of electrolytes and zinc tablets are the treatment of choice and have been estimated to have saved 50 million children in the past 25 years. ORS should be begun at early as possible. Vomiting does often occurs during the first hour or two of treatment with ORS, but this seldom prevents successful rehydration as most of the fluid is still absorbed.
  • the World Health Organization recommends that if a child vomits, to wait five or ten minutes and then start again more slowly.
  • Homemade solutions recommended by WHO include salted drinks (e.g. salted rice water or a salted yoghurt drink) and vegetable or chicken soup with salt. If available, supplemental potassium, as well as supplemental zinc, can be added to or given with this homemade solution. It is s also recommended that persons with diarrhea, if able, continue or resume eating as this speeds recovery of normal intestinal function and generally leads to diarrhea of shorter duration. Clean plain water can be one of several fluids given. There are commercial solutions such as Pedialyte, and relief agencies such as UNICEF widely distribute packets of salts and sugar.
  • secretory diarrhea means that there is an increase in the active secretion, or there is an inhibition of absorption. There is little to no structural damage.
  • the most common cause of this type of diarrhea is a cholera toxin that stimulates the secretion of anions, especially chloride ions.
  • intestinal fluid secretion is isotonic with plasma even during fasting. [8] ⁇ > It continues even when there is no oral food intake.
  • Osmotic diarrhea may occur when too much water is drawn into the bowels. If a person drinks solutions with excessive sugar or excessive salt, these can draw water from the body into the bowel and cause osmotic diarrhea. Also, osmotic diarrhea can also be the result of maldigestion (e.g., pancreatic disease or Coeliac disease), in which the nutrients are left in the lumen to pull in water. Or it can be caused by osmotic laxatives (which work to alleviate constipation by drawing water into the bowels). In healthy individuals, too much magnesium or vitamin C or undigested lactose can produce osmotic diarrhea and distention of the bowel.
  • maldigestion e.g., pancreatic disease or Coeliac disease
  • a person who has lactose intolerance can have difficulty absorbing lactose after an extraordinarily high intake of dairy products. In persons who have fructose malabsorption, excess fructose intake can also cause diarrhea. High-fructose foods that also have a high glucose content are more absorbable and less likely to cause diarrhea. Sugar alcohols such as sorbitol (often found in sugar-free foods) are difficult for the body to absorb and, in large amounts, may lead to osmotic diarrhea. [00019] A third type of diarrhea is exudative diarrhea". Exudative diarrhea occurs with the presence of blood and pus in the stool. This occurs with inflammatory bowel diseases, such as Crohn's disease or ulcerative colitis, and infections such as E. coli or other forms of food poisoning.
  • a fourth type of diarrhea is "motility-related diarrhea”.
  • Motility-related diarrhea is caused by the rapid movement of food through the intestines (hypermotility). If the food moves too quickly through the gastrointestinal tract, there is not enough time for sufficient nutrients and water to be absorbed. This can be due to a vagotomy or diabetic neuropathy, or a complication of menstruation.
  • Hyperthyroidism can produce hypermotility and lead to this type of diarrhea.
  • Diarrhea can be treated with antimotility agents (such as loperamide). Hypermotility can be observed in people who have had portions of their bowel removed, allowing less total time for absorption of nutrients.
  • a fifth type of diarrhea is “is "inflammatory diarrhea is ".
  • Inflammatory diarrhea occurs when there is damage to the mucosal lining or brush border, which leads to a passive loss of protein-rich fluids, and a decreased ability to absorb these lost fluids.
  • Features of all three of the other types of diarrhea can be found in this type of diarrhea. It can be caused by bacterial infections, viral infections, parasitic infections, or autoimmune problems such as inflammatory bowel diseases. It can also be caused by tuberculosis, colon cancer, and enteritis.
  • Dysentery A related condition to diarrhea is "dysentery". Generally, if there is blood visible in the stools, it is not diarrhea, but dysentery. The blood is trace of an invasion of bowel tissue. Dysentery is a symptom of, among others, Shigella, Entamoeba histolytica, and Salmonella.
  • Diarrhea is most commonly due to viral gastroenteritis with rotavirus, which accounts for 40% of cases in children under five. In travelers however bacterial infections predominate. Various toxins such as mushroom poisoning and drugs can also cause acute diarrhea.
  • diarrhea may be classified as chronic or acute. "Chronic diarrhea can be the part of the presentations of a number of chronic medical conditions affecting the intestine. Common causes include ulcerative colitis, Crohn's disease, microscopic colitis, celiac disease, irritable bowel syndrome and bile acid malabsorption.
  • Campylobacter is a common cause of bacterial diarrhea, but infections by Salmonellae, Shigellae and some strains of Escherichia coli (E.coli) are frequent. In the elderly, particularly those who have been treated with antibiotics for unrelated infections, a toxin produced by Clostridium difficile often causes severe diarrhea.
  • Some parasites may cause diarrhea such as the protozoan Giardia, which can cause chronic infections if these are not diagnosed and treated with drugs such as metronidazole, and Entamoeba histolytica.
  • Other causes of chronic diarrhea include: enzyme deficiencies or mucosal abnormality, as in food allergy and food intolerance, e.g. celiac disease (gluten intolerance), lactose intolerance (intolerance to milk sugar, common in non-Europeans), and fructose malabsorption, pernicious anemia, or impaired bowel function due to the inability to absorb vitamin B12, loss of pancreatic secretions, which may be due to cystic fibrosis or pancreatitis, structural defects, like short bowel syndrome (surgically removed bowel) and radiation fibrosis, such as usually follows cancer treatment and other drugs, including agents used in chemotherapy; and certain drugs, like orlistat, which inhibits the absorption of fat.
  • enzyme deficiencies or mucosal abnormality as in food allergy and food intolerance, e.g. celiac disease (gluten intolerance), lactose intolerance (intolerance to milk sugar, common in non-Europeans), and fructose malabsorption, pernicious an
  • Ulcerative colitis is marked by chronic bloody diarrhea and inflammation mostly affects the distal colon near the rectum. Crohn's disease typically affects fairly well demarcated segments of bowel in the colon and often affects the end of the small bowel.
  • IBS irritable bowel syndrome
  • Symptoms of diarrhea- predominant IBS can be managed through a combination of dietary changes, soluble fiber supplements, and/or medications such as loperamide or codeine.
  • About 30% of patients with diarrhea-predominant IBS have bile acid malabsorption diagnosed with an abnormal SeHCAT test.
  • Medications such as loperamide (Imodium) and bismuth subsalicylate may be beneficial in treating some diarrhea conditions, however they may be contraindicated in certain situations.
  • antibiotics are beneficial in certain types of acute diarrhea, they are usually not used except in specific situations. In fact, antibiotics can also cause diarrhea, and antibiotic-associated diarrhea is the most common adverse effect of treatment with general antibiotics.
  • Bismuth compounds such as in (Pepto-Bismol) may be used to treat some diarrhea conditions.
  • anti motility agents may be used to treat some diarrhea conditions. These include loperamide. Codeine is sometimes used in the treatment of diarrhea to slow down peristalsis and the passage of fecal material through the bowels.
  • bile acid sequestrants such as cholestyramine, colestipol and colesevelam can be effective in chronic diarrhea due to bile acid malabsorption.
  • Zinc supplementation may be used to treat some chronic diarrhea conditions.
  • Probiotics may sometimes be used to reduce the duration of symptoms.
  • a second type of diarrhea is acute diarrhea.
  • the most common cause of acute diarrhea is infection—viral, bacterial, and parasitic. Bacteria also can cause acute food poisoning.
  • a third important cause of acute diarrhea is starting a new medication.
  • viral gastroenteritis which is the most common cause of acute diarrhea worldwide. Viral gastroenteritis can occur in a sporadic form (in a single individual) or in an epidemic form (among groups of individuals). Sporadic diarrhea probably is caused by several different viruses and is believed to be spread by person-to-person contact. The most common cause of epidemic diarrhea (for example, on cruise ships) is infection with a family of viruses known as caliciviruses of which the genus norovirus is the most common (for example, "Norwalk agent"). The caliciviruses are transmitted by food that is contaminated by sick food- handlers or by person-to-person contact.
  • Another cause of acute diarrhea is food poisoning caused by toxins produced by bacteria.
  • the toxins cause abdominal pain (cramps) and vomiting and also cause the small intestine to secrete large amounts of water that leads to diarrhea.
  • the symptoms of food poisoning usually last less than 24 hours. With some bacteria, the toxins are produced in the food before it is eaten, while with other bacteria, the toxins are produced in the intestine after the food is eaten.
  • Staphylococcus aureus is an example of a bacterium that produces toxins in food before it is eaten.
  • food contaminated with Staphylococcus such as salad, meat or sandwiches with mayonnaise
  • the Staphylococcal bacteria multiply in the food and produce toxins.
  • Clostridium perfringens is an example of a bacterium that multiplies in food (usually canned food), and produces toxins in the small intestine after the contaminated food is eaten.
  • Another cause of acute diarrhea is traveler's diarrhea usually caused by pathogenic strains of E. coli bacteria. Occasionally, other bacteria or parasites can cause diarrhea in travelers (for example, Shigella, Giardia, Campylobacter). Diarrhea caused by these other organisms usually lasts longer than 3 days.
  • Bacterial enterocolitis is characterized by signs of inflammation (blood or pus in the stool, fever) and abdominal pain and diarrhea.
  • Campylobacter jejuni is the most common bacterium that causes acute enterocolitis in the U.S.
  • Other bacteria that cause enterocolitis include Shigella, Salmonella, and EPEC. These bacteria usually are acquired by drinking contaminated water or eating contaminated foods such as vegetables, poultry, and dairy products.
  • Clostridium difficile is often is caused by antibiotic treatment. Clostridium difficile is also the most common nosocomial infection (infection acquired while in the hospital) to cause diarrhea. Unfortunately, infection also is increasing among individuals who have neither taken antibiotics or been in the hospital.
  • E. coli 0157:H7 Another cause of acute diarrhea is E. coli 0157:H7 which is a strain of E. coli that produces a toxin that causes hemorrhagic enterocolitis (enterocolitis with bleeding).
  • hemorrhagic enterocolitis enterocolitis with bleeding.
  • HUS hemolytic uremic syndrome
  • Still anther cause of acute diarrhea is parasite infection, more common outside of the U. S.
  • infection with Giardia lamblia occurs among individuals who hike in the mountains or travel abroad and is transmitted by contaminated drinking water.
  • Cryptosporidium is another diarrhea-producing parasite that is typically spread by contaminated water.
  • anther cause of acute diarrhea is drug-induced diarrhea.
  • the medications that most frequently cause diarrhea are antacids and nutritional supplements that contain magnesium.
  • Other classes of medication that cause diarrhea include: nonsteroidal antiinflammatory drugs (NSAIDs), chemotherapy medications, antibiotics, medications to control irregular heartbeats (antiarrhythmics), and medications for high blood pressure, misoprostol (Cytotec), quinidine (Quinaglute, Quinidex), olsalazine (Dipentum), colchicine (Colchicine), metoclopramide (Reglan), and cisapride (Propulsid, Motilium).
  • NSAIDs nonsteroidal antiinflammatory drugs
  • chemotherapy medications include antibiotics, antibiotics to control irregular heartbeats (antiarrhythmics), and medications for high blood pressure, misoprostol (Cytotec), quinidine (Quinaglute, Quinidex), olsalazine (Dipentum), colchicine (Colchicine), metoclo
  • Common causes of chronic diarrhea include irritable bowel syndrome, infectious diseases such as Giardia lamblia, AIDS infection, bacterial overgrowth of the small intestine, .post-infectious diarrhea wherein individuals following acute viral, bacterial or parasitic infections develop chronic diarrhea (also referred to as post-infectious IBS), inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, and other diseases causing inflammation of the small intestine and/or colon, commonly cause chronic diarrhea, colon cancer, particularly in the distal part of the colon, can lead to thin stools, severe constipation, carbohydrate (sugar) malabsorption, such as lactase deficiency (also known as lactose or milk intolerance), fat malabsorption pancreatitis or pancreatic cancer, diseases of the lining of the small intestine that prevent the absorption of digested fat such as celiac disease, endocrine diseases such as hyperthyroidism or an under-active pituitary or adrenal gland
  • Both acute and chronic diarrhea may involve adverse complications including dehydration resulting from an excessive loss of fluids and electrolytes from the body due to diarrhea.
  • Dehydration is common among adult patients with acute diarrhea who have large amounts of stool, particularly when the intake of fluids is limited by lethargy or is associated with nausea and vomiting and is common in infants and young children who develop viral gastroenteritis or bacterial infection.
  • Moderate to severe dehydration may cause orthostatic hypotension with syncope (fainting upon standing due to a reduced volume of blood, which causes a drop in blood pressure upon standing), a diminished urine output, severe weakness, shock, kidney failure, confusion, acidosis (too much acid in the blood), and even coma.
  • Electrolytes also are lost with water when diarrhea is prolonged or severe, and mineral or electrolyte deficiencies may occur. The most common deficiencies occur with sodium and potassium. Abnormalities of chloride and bicarbonate also may develop. Finally, there may be irritation of the anus due to the frequent passage of watery stool containing irritating substances.
  • the present invention provides methods and medicaments for treating or preventing CGRP associated diarrhea comprising the administration of at least one polypeptide that binds CGRP or the CGRP receptor and/or a polypeptide which inhibits the CGRP/CGRP receptor interaction.
  • These polypeptides include anti-CGRP or anti-CGRP receptor antibodies and antibody fragments, and fragments or variants of CGRP or the CGRP receptor which inhibit the CGRP/CGRP receptor interaction.
  • These therapies effectively treat or prevent diarrhea, especially diarrhea that occurs as a result of disease conditions or treatments associated with increased levels of CGRP, e.g. increased levels in the gastrointestinal system and more particularly the colon.
  • the invention in particular relates to methods of inhibiting, preventing or treating diarrhea and/or maintaining electrolyte balance and fluid levels in the colon of a subject having a condition (e.g., gastrointestinal condition, cancer, viral or infectious disorder) or treatments associated resulting in elevated CGRP levels (such as radiation or chemotherapy) that result in diarrhea and/or increased flux of electrolytes and fluids from the colon comprising administering an effective amount of an anti-CGRP antibody or anti- CGRP antibody fragment.
  • a condition e.g., gastrointestinal condition, cancer, viral or infectious disorder
  • treatments associated resulting in elevated CGRP levels such as radiation or chemotherapy
  • These conditions include by way of example functional bowel disorders and inflammatory bowel diseases, bacterial or viral induced diarrhea, radiation and chemotherapies and more specifically functional bowel disorders selected from the group consisting of gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, functional abdominal pain syndrome, diverticulosis, and diverticulitis, inflammatory bowel diseases selected from the group consisting of Crohn's disease, ileitis, collagenous colitis, lymphocytic colitis, and ulcerative colitis, and cancers associated with diarrhea such as medullary thyroid carcinoma, and colorectal cancer.
  • functional bowel disorders and inflammatory bowel diseases selected from the group consisting of gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, functional abdominal pain syndrome, diverticulosis, and diverticulitis
  • inflammatory bowel diseases selected from the group consisting of Crohn's disease, ileitis, collagenous colitis, lymphocytic colitis, and ulcerative colitis
  • the invention also relates to methods of screening antibodies and fragments thereof (including Fab fragments) having binding specificity to human Calcitonin Gene Related Peptide (hereinafter "CGRP") or the CGRP receptor or which inhibit the CGRP/CGRP receptor interaction in animal models to determine the in vivo effects thereof, especially their ability to antagonize the adverse side effects of CGRP and to treat or prevent diarrhea in conditions or treatments involving excess CGRP.
  • CGRP Calcitonin Gene Related Peptide
  • the invention involves a method of assessing the potential in vivo efficacy of a candidate anti-CGRP antibody or antibody fragment or another polypeptide that inhibits the CGRP/CGRP receptor interaction for treating or preventing diarrhea comprising determining whether the antibody or other polypeptide inhibits diarrhea in a rodent administered exogenous CGRP compared to a rodent administered CGRP in the absence of the candidate CGRP antibody or antibody fragment or other polypeptide inhibitor.
  • the invention involves a method of administering an anti-CGRP or anti- CGRP receptor antibody or antibody fragment or another polypeptide that inhibits the CGRP/CGRP receptor interaction to treat neurological and pain conditions characterized by increased CGRP levels which are associated with diarrhea.
  • the invention relates to medicaments for treating a condition associated with diarrhea selected from gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, functional abdominal pain syndrome, diverticulosis, diverticulitis, Crohn's disease, ileitis, collagenous colitis, lymphocytic colitis, and ulcerative colitis, medullary thyroid carcinoma or a colorectal cancer.
  • a condition associated with diarrhea selected from gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, functional abdominal pain syndrome, diverticulosis, diverticulitis, Crohn's disease, ileitis, collagenous colitis, lymphocytic colitis, and ulcerative colitis, medullary thyroid carcinoma or a colorectal cancer.
  • the invention relates to methods of assessing based on results in a rodent CGRP animal model a suitable therapeutic dosage or dosage regimen of the candidate antibody or antibody fragment in humans for preventing or treating CGRP associated diarrhea.
  • compositions for inhibiting, preventing or treating diarrhea and/or maintaining electrolyte balance and fluid levels in the colon of a subject having a condition associated with elevated CGRP levels that result in diarrhea and/or increased flux of electrolytes and fluids from the colon comprising an effective amount of an anti-CGRP or anti-CGRP receptor antibody or anti-CGRP or anti-CGRP receptor antibody fragment and optionally another active agent.
  • compositions for treating or preventing functional bowel disorders or an inflammatory bowel diseases, bacterial or viral induced diarrhea, cancer associated with diarrhea, such as medullary thyroid carcinoma or a colorectal cancer, and functional bowel disorders or inflammatory bowel diseases, including by way of example gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, functional abdominal pain syndrome, diverticulosis, and diverticulitis or inflammatory bowel disease is selected from the group consisting of Crohn's disease, ileitis, collagenous colitis, lymphocytic colitis, and ulcerative colitis, wherein these therapies administer an effective amount of an anti-CGRP antibody or antibody fragment which is administered as a monotherapy or in combination with another active agent.
  • the present invention is directed to therapeutic usage of specific antibodies and fragments thereof for treatment or prevention of diarrhea in diseases or treatments associated with in increased levels of CGRP, said antibodies or antibody fragments having binding specificity for CGRP, in particular antibodies having desired epitopic specificity, high affinity or avidity and/or functional properties.
  • this invention relates to assays and usage of the antibodies described herein, comprising the sequences of the V H , V L and CDR polypeptides described herein, and the polynucleotides encoding them.
  • a preferred embodiment of the invention is directed to chimeric or humanized antibodies and fragments thereof (including Fab fragments) capable of binding to CGRP and/or inhibiting the biological activities mediated by the binding of CGRP to the CGRP receptor ("CGRP-R").
  • CGRP-R CGRP receptor
  • the assays and therapies use full length antibodies and Fab fragments thereof for treatment or prevention of diarrhea in diseases or conditions resulting in increased levels of CGRP that inhibit the CGRP-alpha-, CGRP -beta-, and rat CGRP-driven production of cAMP.
  • full length and Fab fragments thereof are contemplated that reduce vasodilation in a recipient following administration.
  • chimeric or humanized antibodies and fragments thereof capable of binding to CGRP or the CGRP receptor are useful in methods directed to reducing, treating, or preventing diarrhea in diseases or conditions resulting in increased levels of CGRP such as migraines (with or without aura), cancer or tumors, angiogenesis associated with cancer or tumor growth, angiogenesis associated with cancer or tumor survival, weight loss, pain, hemiplagic migraines, cluster headaches, migrainous neuralgia, chronic headaches, tension headaches, general headaches, hot flushes, chronic paroxysomal hemicrania, secondary headaches due to an underlying structural problem in the head or neck, cranial neuralgia, sinus headaches (such as for example associated with sinusitis), and allergy-induced headaches or migraines.
  • migraines with or without aura
  • cancer or tumors angiogenesis associated with cancer or tumor growth
  • angiogenesis associated with cancer or tumor survival weight loss
  • pain, hemiplagic migraines cluster headaches
  • migrainous neuralgia chronic headaches
  • chimeric or humanized antibodies and fragments thereof capable of binding to CGRP are useful in methods directed to reducing, treating, or preventing diarrhea and visceral pain associated with gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, ileitis, ulcerative colitis, renal colic, dysmenorrhea, cystitis, menstrual period, labor, menopause, prostatitis, or pancreatitis.
  • these antibodies and humanized versions for treatment or prevention of diarrhea in diseases or conditions resulting in increased levels of CGRP may be derived from rabbit immune cells (B lymphocytes) and may be selected based on their homology (sequence identity) to human germ line sequences. These antibodies may require minimal or no sequence modifications, thereby facilitating retention of functional properties after humanization.
  • a further embodiment of the invention is directed to fragments from anti-CGRP antibodies encompassing V H , V L and CDR polypeptides, e.g., derived from rabbit immune cells and the polynucleotides encoding the same, as well as the use of these antibody fragments and the polynucleotides encoding them in the creation of novel antibodies and polypeptide compositions capable of binding to CGRP and/or CGRP/CGRP-R complexes for treatment or prevention of diarrhea in diseases or conditions resulting in increased levels of CGRP.
  • V H , V L and CDR polypeptides e.g., derived from rabbit immune cells and the polynucleotides encoding the same, as well as the use of these antibody fragments and the polynucleotides encoding them in the creation of novel antibodies and polypeptide compositions capable of binding to CGRP and/or CGRP/CGRP-R complexes for treatment or prevention of diarrhea in diseases or conditions resulting in increased levels of CGRP.
  • the invention also contemplates conjugates of anti-CGRP antibodies and binding fragments thereof conjugated to one or more functional or detectable moieties for treatment or prevention of diarrhea in diseases or conditions resulting in increased levels of CGRP.
  • the invention also contemplates methods of making said chimeric or humanized anti-CGRP or anti-CGRP/CGRP-R complex antibodies and binding fragments thereof for treatment or prevention of diarrhea in diseases or conditions resulting in increased levels of CGRP.
  • binding fragments include, but are not limited to, Fab, Fab', F(ab') 2 , Fv, scFv fragments, SMIPs (small molecule immunopharmaceuticals), camelbodies, nanobodies, and IgNAR.
  • Embodiments of the invention pertain to the use of anti-CGRP antibodies and binding fragments thereof for the diagnosis, assessment and treatment of diseases and disorders associated with CGRP or aberrant expression thereof that result in diarrhea because of increased levels of CGRP.
  • the invention also contemplates the use of fragments of anti-CGRP antibodies for the diagnosis, assessment and treatment of diseases and disorders associated with CGRP or aberrant expression thereof such as diseases or conditions wherein increased levels of CGRP in the gut result in diarrhea.
  • Other embodiments of the invention relate to the production of anti-CGRP antibodies or fragments thereof in recombinant host cells, for example mammalian cells such as CHO, NSO or HEK 293 cells, or yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • Figure 1 provides polynucleotide and polypeptide sequences corresponding to the full-length Antibody Abl .
  • Figure 2 provides polynucleotide and polypeptide sequences corresponding to the full-length Antibody Ab2.
  • Figure 3 provides polynucleotide and polypeptide sequences corresponding to the full-length Antibody Ab3.
  • Figure 4 provides polynucleotide and polypeptide sequences corresponding to the full-length Antibody Ab4.
  • Figure 5 provides polynucleotide and polypeptide sequences corresponding to the full-length Antibody Ab5.
  • Figure 6 provides polynucleotide and polypeptide sequences corresponding to the full-length Antibody Ab6.
  • Figure 7 provides polynucleotide and polypeptide sequences corresponding to the full-length Antibody Ab7.
  • Figure 8 provides polynucleotide and polypeptide sequences corresponding to the full-length Antibody Ab8.
  • Figure 9 provides polynucleotide and polypeptide sequences corresponding to the full-length Antibody Ab9.
  • Figure 10 provides polynucleotide and polypeptide sequences corresponding to the full-length Antibody AblO.
  • Figure 11 provides polynucleotide and polypeptide sequences corresponding to the full-length Antibody Abl 1.
  • Figure 12 provides polynucleotide and polypeptide sequences corresponding to the full-length Antibody Abl 2.
  • Figure 13 provides polynucleotide and polypeptide sequences corresponding to the full-length Antibody Abl3.
  • Figure 14 provides polynucleotide and polypeptide sequences corresponding to the full-length Antibody AM 4.
  • Figure 15 provides the CGRP-alpha ELISA binding data obtained following the protocol in Example 1 infra for antibodies Abl, Ab2, Ab3, and Ab4.
  • Figure 16 provides the CGRP-alpha ELISA binding data obtained following the protocol in Example 1 infra for antibodies Ab5, Ab6, Ab7, and Ab8.
  • Figure 17 provides the CGRP-alpha ELISA binding data obtained following the protocol in Example 1 infra for antibodies Ab9, AblO, and AM4.
  • Figure 18 provides the CGRP-alpha ELISA binding data obtained following the protocol in Example 1 infra for antibodies Abl 1, Abl 2, and AM3.
  • Figure 19 demonstrates the inhibition of CGRP-alpha-driven cAMP production by antibodies Abl, Ab2, and Ab4, obtained following the protocol in Example 1 infra.
  • Figure 20 demonstrates the inhibition of CGRP-alpha-driven cAMP production by antibody Ab3, obtained following the protocol in Example 1 infra.
  • Figure 21 demonstrates the inhibition of CGRP-alpha-driven cAMP production by antibodies Ab5 and Ab6, obtained following the protocol in Example 1 infra.
  • Figure 22 demonstrates the inhibition of CGRP-alpha-driven cAMP production by antibodies Ab7, Ab8, Ab9, and AblO, obtained following the protocol in Example 1 infra.
  • Figure 23 demonstrates the inhibition of CGRP-alpha-driven cAMP production by antibodies Abl 1, Abl 2, and Abl 3, obtained following the protocol in Example 1 infra.
  • Figure 24 demonstrates the inhibition of CGRP-alpha-driven cAMP production by antibody Abl 4, obtained following the protocol in Example 1 infra.
  • Figure 25 demonstrates the inhibition of CGRP -beta-driven cAMP production by antibodies Abl, Ab2, and Ab3, obtained following the protocol in Example 1 infra.
  • Figure 26 demonstrates the inhibition of CGRP -beta-driven cAMP production by antibodies Ab4, Ab5, and Ab6, obtained following the protocol in Example 1 infra.
  • Figure 27 demonstrates the inhibition of CGRP -beta-driven cAMP production by antibodies Ab7 and Ab8, obtained following the protocol in Example 1 infra.
  • Figure 28 demonstrates the inhibition of CGRP -beta-driven cAMP production by antibodies Ab9, AblO, and Abl4, obtained following the protocol in Example 1 infra.
  • Figure 29 demonstrates the inhibition of CGRP -beta-driven cAMP production by antibodies Abl 1, Abl2, and Abl3, obtained following the protocol in Example 1 infra.
  • Figure 30 demonstrates the inhibition of rat CGRP-driven cAMP production by antibodies Abl, Ab2, Ab4, and Ab5, obtained following the protocol in Example 1 infra.
  • Figure 31 demonstrates the inhibition of rat CGRP -driven cAMP production by antibodies Ab3 and Ab6, obtained following the protocol in Example 1 infra.
  • Figure 32 demonstrates the inhibition of rat CGRP-driven cAMP production by antibodies Ab7 and Ab8, obtained following the protocol in Example 1 infra.
  • Figure 33 demonstrates the inhibition of rat CGRP-driven cAMP production by antibody Ab9, obtained following the protocol in Example 1 infra.
  • Figure 34 demonstrates the inhibition of rat CGRP-driven cAMP production by antibody AblO, obtained following the protocol in Example 1 infra.
  • Figure 35 demonstrates the inhibition of rat CGRP-driven cAMP production by antibodies Abl 1 and Abl 2, obtained following the protocol in Example 1 infra.
  • Figure 36 demonstrates the inhibition of rat CGRP-driven cAMP production by antibody Abl 3, obtained following the protocol in Example 1 infra.
  • Figure 37 demonstrates the inhibition of rat CGRP-driven cAMP production by antibody Abl 4, obtained following the protocol in Example 1 infra.
  • Figure 38 demonstrates the inhibition of binding of radiolabeled CGRP to CGRP-R by antibodies Abl -Abl 3, obtained following the protocol in Example 6 infra.
  • Figure 39 demonstrates a reduction in vasodilation obtained by administering antibodies Ab3 and Ab6 following capsaicin administration in a rat model, relative to a control antibody, obtained following the protocol in Example 7 infra.
  • Figure 40 demonstrates a reduction in vasodilation obtained by administering antibody Ab6 at differing concentrations following capsaicin administration in a rat model, relative to a control antibody, obtained following the protocol in Example 7 infra.
  • Figure 41 contains the results of experiments wherein the effects of CGRP in transgenic Nestin/hRampl mice were evaluated.
  • the data shows that rat CGRP-alpha administration induced diarrhea in Nestin/hRAMPl tg mice and that the intra peritoneal injection of Ab3 (30mgs/kg, ⁇ 24 hrs. prior to CGRP challenge) inhibits intra cerebroventricular (ICV) injected, rat CGRP-alpha induced diarrhea in Nestin/hRAMPl tg mice.
  • ICV cerebroventricular
  • Figure 42 contains the results of experiments which show that the intra cerebroventricular (ICV) injection of human CGRP-alpha induces diarrhea in a dose dependent manner in C57BL/6J mice.
  • ICV intra cerebroventricular
  • Figure 43 contains the results of experiments which show that intra peritoneal injection of Ab3 (30mgs/kg ip, ⁇ 24 hrs. prior to human CGRP-alpha challenge) inhibits ICV injected human CGRP-alpha induced diarrhea in C57/BL6J mice.
  • Figure 44 contains the results of experiments which show that Ab3 (30mgs/kg ip injection ⁇ 24 hrs. prior to human CGRP-alpha challenge) inhibits IP injected- human CGRP-alpha induced diarrhea in C57/BL6J mice.
  • FIG. 45 shows prevention of CGRP-induced diarrhea by Ab3 and Ab6 (both administered at 10 mg/kg). Negative control animals (treated with a control antibody and phosphate buffered saline, left bar) did not exhibit diarrhea, and 80% of positive control animals (treated with CGRP and a negative control antibody, filled bar) exhibited diarrhea. Administration of Ab3 (diagonal striped bar) and Ab6 (cross-hatched bar) reduced incidence of diarrhea to 40%> and 60%>, respectively.
  • FIG. 46 shows gross fecal weight resulting from CGRP-induced diarrhea for the experiment shown in FIG. 45. Gross fecal weight was greatly increased by administration of CGRP (second bar) compared to negative control animals (first bar). However, Ab3- and Ab6-treated animals exhibited greatly reduced gross fecal weight (third and fourth bars, respectively). Values shown are the average of all animals in each test group plus or minus standard error of mean (SEM). [000113] FIG. 47 confirms prevention of CGRP -induced diarrhea by Ab3 and Ab6 in a further experiment (both antibodies administered at 30 mg/kg).
  • Diarrhea was absent in negative control animals (treated with a control antibody and phosphate buffered saline, first bar) but observed in 80% of positive control animals (second bar, filled). Diarrhea incidence was reduced to 20% and 40%>, respectively by Ab3 (third bar, diagonal stripes) and Ab6 (fourth bar, Crosshatch).
  • FIG. 48 shows gross fecal weight resulting from CGRP-induced diarrhea for the experiment shown in FIG. 47.
  • Gross fecal weight was greatly increased by administration of CGRP (second bar, filled) compared to negative control animals (first bar, unfilled).
  • Ab6-treated animals exhibited greatly reduced gross fecal weight (fourth bar, checkered), and Ab3-treated animals (third bar, Crosshatch) exhibited average gross fecal weight comparable to negative control animals (left bar, unfilled). Values shown are the average of all animals in each test group plus or minus standard error of mean (SEM).
  • CGRP Calcitonin Gene Related Peptide
  • CGRP-alpha ACDTATCVTHRLAGLLSRSGGVVKNNFVPTNVGSKAF- NH2 (SEQ ID NO: 281), wherein the N-terminal phenylalanine is amidated;
  • CGRP-beta ACNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF-NH2 (SEQ ID NO: 282), wherein the N-terminal phenylalanine is amidated; but also any membrane-bound forms of these CGRP amino acid sequences, as well as mutants (mutiens), splice variants, isoforms, orthologues, homologues and variants of this sequence.
  • CGRP herein encompasses rodent CGRPs and CGRP sequences of other mammals.
  • CGRP receptor herein includes all endogenous receptors that are specifically bound by CGRP, including human and rodent CGRP and other mammalian CGRP.
  • CGRP receptor includes mutants (mutiens), splice variants, isoforms, orthologues, homologues, fragments and variants of CGRP receptors that are specifically bound by CGRP.
  • CGRP receptor herein encompasses human, rat, murine and non- human primate CGRP receptors and CGRP receptor sequences of other mammals.
  • CGRP/CGRP Receptor Inhibitor refers to a molecule, preferably a polypeptide such as an antibody or antibody fragment that inhibits the interaction of CGRP and its receptor.
  • Non-limiting examples thereof include antibodies and antibody fragments that specifically bind CGRP or the CGRP receptor and fragments of CGRP or the CGRP receptor.
  • Diarrhea refers to an increase in the frequency of bowel movements or a decrease in the form of stool (greater looseness of stool). Although changes in frequency of bowel movements and looseness of stools can vary independently of each other, changes often occur in both. Diarrhea needs to be distinguished from four other conditions. Although these conditions may accompany diarrhea, they often have different causes and different treatments than diarrhea.
  • incontinence of stool which is the inability to control (delay) bowel movements until an appropriate time, for example, until one can get to the toilet
  • rectal urgency which is a sudden urge to have a bowel movement that is so strong that if a toilet is not immediately available there will be incontinence
  • incomplete evacuation which is a sensation that another bowel movement is necessary soon after a bowel movement, yet there is difficulty passing further stool the second time and bowel movements immediately after eating a meal.
  • Diarrhea can be defined in absolute or relative terms based on either the frequency of bowel movements or the consistency (looseness) of stools.
  • Diarrhea generally is divided into two types, acute and chronic. Acute diarrhea lasts from a few days up to a week. Chronic diarrhea can be defined in several ways but almost always lasts more than three weeks. Acute and chronic diarrhea usually have different causes, require different diagnostic tests, and often involve different treatments.
  • Treatment or prevention of CGRP -induced diarrhea means that the treatment, e.g., administration of an anti-CGRP antibody or fragment effectively inhibits or treats diarrhea and/or maintains proper electrolyte and fluid levels in the colon of a subject in need thereof relative to an untreated subject.
  • CGRP-induced diarrhea or CGRP-associated diarrhea refers to a condition or treatment resulting in elevated CGRP levels, especially in the gastrointestinal system and especially the colon that result in one or more of increased excretion of fluid from the colon, impaired electrolyte balance and one or more watery bowel movements (diarrhea).
  • Treatments that result in CGRP-associated diarrhea refer to any treatment for a disease condition, e.g., radiation, chemotherapy, drug therapy that result in increased CGRP levels that are associated with diarrhea.
  • 'CGRP associated disease or condition is any disease or condition that is associated with increased CGRP levels relative to CGRP levels in normal individuals.
  • Mating competent yeast species In the present invention this is intended to broadly encompass any diploid or tetraploid yeast which can be grown in culture. Such species of yeast may exist in a haploid, diploid, or other polyploid form. The cells of a given ploidy may, under appropriate conditions, proliferate for an indefinite number of generations in that form. Diploid cells can also sporulate to form haploid cells. Sequential mating can result in tetraploid strains through further mating or fusion of diploid strains. The present invention contemplates the use of haploid yeast, as well as diploid or other polyploid yeast cells produced, for example, by mating or spheroplast fusion.
  • the mating competent yeast is a member of the Saccharomycetaceae family, which includes the genera Arxiozyma; Ascobotryozyma; Citeromyces; Debaryomyces; Dekkera; Eremothecium; Issatchenkia; Kazachstania; Kluyveromyces; Kodamaea; Lodderomyces; Pachysolen; Pichia; Saccharomyces; Saturnispora; Tetrapisispora; Torulaspora; Williopsis; and Zygosaccharomyces.
  • Other types of yeast potentially useful in the invention include Yarrowia; Rhodosporidium; Candida; Hansenula; Filobasium; Sporidiobolus; Bullera; Leucosporidium and Filobasidella.
  • the mating competent yeast is a member of the genus Pichia.
  • the mating competent yeast of the genus Pichia is one of the following species: Pichia pastoris, Pichia methanolica, and Hansenula polymorpha (Pichia angusta).
  • the mating competent yeast of the genus Pichia is the species Pichia pastoris.
  • Haploid Yeast Cell A cell having a single copy of each gene of its normal genomic (chromosomal) complement.
  • Polyploid Yeast Cell A cell having more than one copy of its normal genomic (chromosomal) complement.
  • Diploid Yeast Cell A cell having two copies (alleles) of essentially every gene of its normal genomic complement, typically formed by the process of fusion (mating) of two haploid cells.
  • Tetraploid Yeast Cell A cell having four copies (alleles) of essentially every gene of its normal genomic complement, typically formed by the process of fusion (mating) of two haploid cells. Tetraploids may carry two, three, four or more different expression cassettes. Such tetraploids might be obtained in S. cerevisiae by selective mating homozygotic heterothallic a/a and alpha/alpha diploids and in Pichia by sequential mating of haploids to obtain auxotrophic diploids.
  • a [met his] haploid can be mated with [ade his] haploid to obtain diploid [his]; and a [met arg] haploid can be mated with [ade arg] haploid to obtain diploid [arg]; then the diploid [his] x diploid [arg] to obtain a tetraploid prototroph. It will be understood by those of skill in the art that reference to the benefits and uses of diploid cells may also apply to tetraploid cells.
  • Yeast Mating The process by which two haploid yeast cells naturally fuse to form one diploid yeast cell.
  • Meiosis The process by which a diploid yeast cell undergoes reductive division to form four haploid spore products. Each spore may then germinate and form a haploid vegetatively growing cell line.
  • a selectable marker is a gene or gene fragment that confers a growth phenotype (physical growth characteristic) on a cell receiving that gene as, for example through a transformation event.
  • the selectable marker allows that cell to survive and grow in a selective growth medium under conditions in which cells that do not receive that selectable marker gene cannot grow.
  • Selectable marker genes generally fall into several types, including positive selectable marker genes such as a gene that confers on a cell resistance to an antibiotic or other drug, temperature when two temperature sensitive ("ts") mutants are crossed or a ts mutant is transformed; negative selectable marker genes such as a biosynthetic gene that confers on a cell the ability to grow in a medium without a specific nutrient needed by all cells that do not have that biosynthetic gene, or a mutagenized biosynthetic gene that confers on a cell inability to grow by cells that do not have the wild type gene; and the like. Suitable markers include but are not limited to: ZEO; G418; LYS3; MET1; MET3a; ADE1; ADE3; URA3; and the like.
  • Expression Vector These DNA vectors contain elements that facilitate manipulation for the expression of a foreign protein within the target host cell. Conveniently, manipulation of sequences and production of DNA for transformation is first performed in a bacterial host, e.g. E. coli, and usually vectors will include sequences to facilitate such manipulations, including a bacterial origin of replication and appropriate bacterial selection marker. Selection markers encode proteins necessary for the survival or growth of transformed host cells grown in a selective culture medium. Host cells not transformed with the vector containing the selection gene will not survive in the culture medium. Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, (b) complement auxotrophic deficiencies, or (c) supply critical nutrients not available from complex media.
  • Exemplary vectors and methods for transformation of yeast are described, for example, in Burke, D., Dawson, D., & Stearns, T. (2000). Methods in yeast genetics: a Cold Spring Harbor Laboratory course manual. Plainview, N.Y.: Cold Spring Harbor Laboratory Press.
  • Expression vectors for use in the methods of the invention will further include yeast specific sequences, including a selectable auxotrophic or drug marker for identifying transformed yeast strains.
  • a drug marker may further be used to amplify copy number of the vector in a yeast host cell.
  • the polypeptide coding sequence of interest is operably linked to transcriptional and translational regulatory sequences that provide for expression of the polypeptide in yeast cells.
  • These vector components may include, but are not limited to, one or more of the following: an enhancer element, a promoter, and a transcription termination sequence. Sequences for the secretion of the polypeptide may also be included, e.g. a signal sequence, and the like.
  • a yeast origin of replication is optional, as expression vectors are often integrated into the yeast genome.
  • the polypeptide of interest is operably linked, or fused, to sequences providing for optimized secretion of the polypeptide from yeast diploid cells.
  • Nucleic acids are "operably linked" when placed into a functional relationship with another nucleic acid sequence.
  • DNA for a signal sequence is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence.
  • "operably linked” means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading frame. However, enhancers do not have to be contiguous.
  • Linking is accomplished by ligation at convenient restriction sites or alternatively via a PCR/recombination method familiar to those skilled in the art (GatewayR Technology; Invitrogen, Carlsbad California). If such sites do not exist, the synthetic oligonucleotide adapters or linkers are used in accordance with conventional practice.
  • Promoters are untranslated sequences located upstream (5') to the start codon of a structural gene (generally within about 100 to 1000 bp) that control the transcription and translation of particular nucleic acid sequences to which they are operably linked.
  • Such promoters fall into several classes: inducible, constitutive, and repressible promoters (that increase levels of transcription in response to absence of a repressor).
  • Inducible promoters may initiate increased levels of transcription from DNA under their control in response to some change in culture conditions, e.g., the presence or absence of a nutrient or a change in temperature.
  • the yeast promoter fragment may also serve as the site for homologous recombination and integration of the expression vector into the same site in the yeast genome; alternatively a selectable marker is used as the site for homologous recombination. Pichia transformation is described in Cregg et al. (1985) Mol. Cell. Biol. 5:3376-3385.
  • Suitable promoters from Pichia include the AOX1 and promoter (Cregg et al. (1989) Mol. Cell. Biol. 9: 1316-1323); ICL1 promoter (Menendez et al. (2003) Yeast 20(13): 1097-108); glyceraldehyde-3 -phosphate dehydrogenase promoter (GAP) (Waterham et al. (1997) Gene 186(l):37-44); and FLD1 promoter (Shen et al. (1998) Gene 216(1):93-102).
  • the GAP promoter is a strong constitutive promoter and the AOX and FLD1 promoters are inducible.
  • yeast promoters include ADH1, alcohol dehydrogenase II, GAL4, PH03, PH05, Pyk, and chimeric promoters derived therefrom.
  • non-yeast promoters may be used in the invention such as mammalian, insect, plant, reptile , amphibian, viral, and avian promoters. Most typically the promoter will comprise a mammalian promoter (potentially endogenous to the expressed genes) or will comprise a yeast or viral promoter that provides for efficient transcription in yeast systems.
  • the polypeptides of interest may be produced recombinantly not only directly, but also as a fusion polypeptide with a heterologous polypeptide, e.g. a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide.
  • a heterologous polypeptide e.g. a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide.
  • the signal sequence may be a component of the vector, or it may be a part of the polypeptide coding sequence that is inserted into the vector.
  • the heterologous signal sequence selected preferably is one that is recognized and processed through one of the standard pathways available within the host cell.
  • the S. cerevisiae alpha factor pre-pro signal has proven effective in the secretion of a variety of recombinant proteins from P. pastoris.
  • yeast signal sequences include the alpha mating factor signal sequence, the invertase signal sequence, and signal sequences derived from other secreted yeast polypeptides. Additionally, these signal peptide sequences may be engineered to provide for enhanced secretion in diploid yeast expression systems. Other secretion signals of interest also include mammalian signal sequences, which may be heterologous to the protein being secreted, or may be a native sequence for the protein being secreted. Signal sequences include pre-peptide sequences, and in some instances may include propeptide sequences.
  • signal sequences are known in the art, including the signal sequences found on immunoglobulin chains, e.g., K28 preprotoxin sequence, PHA-E, FACE, human MCP-1, human serum albumin signal sequences, human Ig heavy chain, human Ig light chain, and the like.
  • K28 preprotoxin sequence e.g., PHA-E, FACE, human MCP-1, human serum albumin signal sequences, human Ig heavy chain, human Ig light chain, and the like.
  • Transcription may be increased by inserting a transcriptional activator sequence into the vector.
  • These activators are cis-acting elements of DNA, usually about from 10 to 300 bp, which act on a promoter to increase its transcription.
  • Transcriptional enhancers are relatively orientation and position independent, having been found 5' and 3' to the transcription unit, within an intron, as well as within the coding sequence itself. The enhancer may be spliced into the expression vector at a position 5' or 3' to the coding sequence, but is preferably located at a site 5' from the promoter.
  • Expression vectors used in eukaryotic host cells may also contain sequences necessary for the termination of transcription and for stabilizing the mR A. Such sequences are commonly available from 3' to the translation termination codon, in untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA.
  • Plasmids from the transformants are prepared, analyzed by restriction endonuclease digestion and/or sequenced.
  • recombination methods based on att sites and recombination enzymes may be used to insert DNA sequences into a vector. Such methods are described, for example, by Landy (1989) Ann.Rev.Biochem. 58:913-949; and are known to those of skill in the art. Such methods utilize intermolecular DNA recombination that is mediated by a mixture of lambda and E.coli -encoded recombination proteins. Recombination occurs between specific attachment (att) sites on the interacting DNA molecules.
  • Att sites may be introduced into a sequence of interest by ligating the sequence of interest into an appropriate vector; generating a PCR product containing att B sites through the use of specific primers; generating a cDNA library cloned into an appropriate vector containing att sites; and the like.
  • Folding refers to the three-dimensional structure of polypeptides and proteins, where interactions between amino acid residues act to stabilize the structure. While non-covalent interactions are important in determining structure, usually the proteins of interest will have intra- and/or intermolecular covalent disulfide bonds formed by two cysteine residues. For naturally occurring proteins and polypeptides or derivatives and variants thereof, the proper folding is typically the arrangement that results in optimal biological activity, and can conveniently be monitored by assays for activity, e.g. ligand binding, enzymatic activity, etc.
  • the expression host may be further modified by the introduction of sequences encoding one or more enzymes that enhance folding and disulfide bond formation, i.e. foldases, chaperonins, etc.
  • sequences may be constitutively or inducibly expressed in the yeast host cell, using vectors, markers, etc. as known in the art.
  • sequences, including transcriptional regulatory elements sufficient for the desired pattern of expression are stably integrated in the yeast genome through a targeted methodology.
  • the eukaryotic PDI is not only an efficient catalyst of protein cysteine oxidation and disulfide bond isomerization, but also exhibits chaperone activity. Co-expression of PDI can facilitate the production of active proteins having multiple disulfide bonds. Also of interest is the expression of BIP (immunoglobulin heavy chain binding protein); cyclophilin; and the like.
  • BIP immunoglobulin heavy chain binding protein
  • cyclophilin cyclophilin
  • each of the haploid parental strains expresses a distinct folding enzyme, e.g. one strain may express BIP, and the other strain may express PDI or combinations thereof.
  • the terms “desired protein” or “desired antibody” are used interchangeably and refer generally to a parent antibody specific to a target, i.e., CGRP or a chimeric or humanized antibody or a binding portion thereof derived therefrom as described herein.
  • the term “antibody” is intended to include any polypeptide chain-containing molecular structure with a specific shape that fits to and recognizes an epitope, where one or more non-covalent binding interactions stabilize the complex between the molecular structure and the epitope.
  • the archetypal antibody molecule is the immunoglobulin, and all types of immunoglobulins, IgG, IgM, IgA, IgE, IgD, etc., from all sources, e.g.
  • antibodies human, rodent, rabbit, cow, sheep, pig, dog, other mammals, chicken, other avians, etc., are considered to be "antibodies.”
  • a preferred source for producing antibodies useful as starting material according to the invention is rabbits. Numerous antibody coding sequences have been described; and others may be raised by methods well-known in the art. Examples thereof include chimeric antibodies, human antibodies and other non-human mammalian antibodies, humanized antibodies, single chain antibodies (such as scFvs), camelbodies, nanobodies, IgNAR (single-chain antibodies derived from sharks), small-modular immunopharmaceuticals (SMIPs), and antibody fragments such as Fabs, Fab', F(ab')2 and the like.
  • antibodies or antigen binding fragments may be produced by genetic engineering.
  • antibody-producing cells are sensitized to the desired antigen or immunogen.
  • the messenger R A isolated from antibody producing cells is used as a template to make cDNA using PCR amplification.
  • a library of vectors, each containing one heavy chain gene and one light chain gene retaining the initial antigen specificity, is produced by insertion of appropriate sections of the amplified immunoglobulin cDNA into the expression vectors.
  • a combinatorial library is constructed by combining the heavy chain gene library with the light chain gene library. This results in a library of clones which co-express a heavy and light chain (resembling the Fab fragment or antigen binding fragment of an antibody molecule).
  • the vectors that carry these genes are co-transfected into a host cell. When antibody gene synthesis is induced in the transfected host, the heavy and light chain proteins self-assemble to produce active antibodies that can be detected by screening with the antigen or immunogen.
  • Antibody coding sequences of interest include those encoded by native sequences, as well as nucleic acids that, by virtue of the degeneracy of the genetic code, are not identical in sequence to the disclosed nucleic acids, and variants thereof.
  • Variant polypeptides can include amino acid (aa) substitutions, additions or deletions. The amino acid substitutions can be conservative amino acid substitutions or substitutions to eliminate non-essential amino acids, such as to alter a glycosylation site, or to minimize misfolding by substitution or deletion of one or more cysteine residues that are not necessary for function.
  • Variants can be designed so as to retain or have enhanced biological activity of a particular region of the protein (e.g., a functional domain, catalytic amino acid residues, etc).
  • Variants also include fragments of the polypeptides disclosed herein, particularly biologically active fragments and/or fragments corresponding to functional domains. Techniques for in vitro mutagenesis of cloned genes are known. Also included in the subject invention are polypeptides that have been modified using ordinary molecular biological techniques so as to improve their resistance to proteolytic degradation or to optimize solubility properties or to render them more suitable as a therapeutic agent.
  • Chimeric antibodies according to the invention for treatment or prevention of diarrhea in diseases or conditions resulting in increased levels of CGRP may be made by recombinant means by combining the variable light and heavy chain regions (VL and VH), obtained from antibody producing cells of one species with the constant light and heavy chain regions from another.
  • VL and VH variable light and heavy chain regions
  • chimeric antibodies utilize rodent or rabbit variable regions and human constant regions, in order to produce an antibody with predominantly human domains.
  • the production of such chimeric antibodies is well known in the art, and may be achieved by standard means (as described, e.g., in U.S. Patent No. 5,624,659, incorporated herein by reference in its entirety).
  • the human constant regions of chimeric antibodies of the invention may be selected from IgGl, IgG2, IgG3, IgG4, IgG5, IgG6, IgG7, IgG8, IgG9, IgGlO, IgGl l, IgG12, IgG13, IgG14, IgG15, IgGl 6, IgGl 7, IgGl 8 or IgGl 9 constant regions.
  • Humanized antibodies are engineered to contain even more human- like immunoglobulin domains, and incorporate only the complementarity-determining regions of the animal-derived antibody. This is accomplished by carefully examining the sequence of the hyper-variable loops of the variable regions of the monoclonal antibody, and fitting them to the structure of the human antibody chains. Although facially complex, the process is straightforward in practice. See, e.g., U.S. Patent No. 6,187,287, incorporated fully herein by reference.
  • immunoglobulin fragments comprising the epitope binding site (e.g., Fab', F(ab')2, or other fragments) may be synthesized.
  • "Fragment,” or minimal immunoglobulins may be designed utilizing recombinant immunoglobulin techniques.
  • Fv immunoglobulins for use in the present invention may be produced by synthesizing a fused variable light chain region and a variable heavy chain region. Combinations of antibodies are also of interest, e.g. diabodies, which comprise two distinct Fv specificities.
  • SMIPs small molecule immunopharmaceuticals
  • camelbodies, nanobodies, and IgNAR are encompassed by immunoglobulin fragments.
  • Immunoglobulins and fragments thereof may be modified post-trans lationally, e.g. to add effector moieties such as chemical linkers, detectable moieties, such as fluorescent dyes, enzymes, toxins, substrates, bioluminescent materials, radioactive materials, chemiluminescent moieties and the like, or specific binding moieties, such as streptavidin, avidin, or biotin, and the like may be utilized in the methods and compositions of the present invention. Examples of additional effector molecules are provided infra.
  • a "heterologous" region or domain of a DNA construct is an identifiable segment of DNA within a larger DNA molecule that is not found in association with the larger molecule in nature.
  • the gene when the heterologous region encodes a mammalian gene, the gene will usually be flanked by DNA that does not flank the mammalian genomic DNA in the genome of the source organism.
  • Another example of a heterologous region is a construct where the coding sequence itself is not found in nature (e.g., a cDNA where the genomic coding sequence contains introns, or synthetic sequences having codons different than the native gene). Allelic variations or naturally-occurring mutational events do not give rise to a heterologous region of DNA as defined herein.
  • a "coding sequence” is an in-frame sequence of codons that (in view of the genetic code) correspond to or encode a protein or peptide sequence. Two coding sequences correspond to each other if the sequences or their complementary sequences encode the same amino acid sequences. A coding sequence in association with appropriate regulatory sequences may be transcribed and translated into a polypeptide. A polyadenylation signal and transcription termination sequence will usually be located 3' to the coding sequence.
  • a “promoter sequence” is a DNA regulatory region capable of binding RNA polymerase in a cell and initiating transcription of a downstream (3' direction) coding sequence. Promoter sequences typically contain additional sites for binding of regulatory molecules (e.g., transcription factors) which affect the transcription of the coding sequence.
  • a coding sequence is "under the control" of the promoter sequence or "operatively linked” to the promoter when RNA polymerase binds the promoter sequence in a cell and transcribes the coding sequence into mRNA, which is then in turn translated into the protein encoded by the coding sequence.
  • Vectors are used to introduce a foreign substance, such as DNA, RNA or protein, into an organism or host cell.
  • Typical vectors include recombinant viruses (for polynucleotides) and liposomes (for polypeptides).
  • a "DNA vector” is a replicon, such as plasmid, phage or cosmid, to which another polynucleotide segment may be attached so as to bring about the replication of the attached segment.
  • An "expression vector” is a DNA vector which contains regulatory sequences which will direct polypeptide synthesis by an appropriate host cell.
  • Amplification of polynucleotide sequences is the in vitro production of multiple copies of a particular nucleic acid sequence.
  • the amplified sequence is usually in the form of DNA.
  • a variety of techniques for carrying out such amplification are described in a review article by Van Brunt (1990, Bio/Technol., 8(4):291-294).
  • Polymerase chain reaction or PCR is a prototype of nucleic acid amplification, and use of PCR herein should be considered exemplary of other suitable amplification techniques.
  • Antibodies consist of two identical light polypeptide chains of molecular weight approximately 23,000 daltons (the "light chain”), and two identical heavy chains of molecular weight 53,000-70,000 (the “heavy chain”).
  • the four chains are joined by disulfide bonds in a "Y" configuration wherein the light chains bracket the heavy chains starting at the mouth of the "Y” configuration.
  • the "branch” portion of the "Y” configuration is designated the Fab region; the stem portion of the "Y” configuration is designated the FC region.
  • the amino acid sequence orientation runs from the N-terminal end at the top of the "Y" configuration to the C-terminal end at the bottom of each chain.
  • the N-terminal end possesses the variable region having specificity for the antigen that elicited it, and is approximately 100 amino acids in length, there being slight variations between light and heavy chain and from antibody to antibody.
  • the variable region is linked in each chain to a constant region that extends the remaining length of the chain and that within a particular class of antibody does not vary with the specificity of the antibody (i.e., the antigen eliciting it).
  • constant regions that determine the class of the immunoglobulin molecule (IgG, IgM, IgA, IgD, and IgE corresponding to ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ (gamma, mu, alpha, delta, or epsilon) heavy chain constant regions).
  • the constant region or class determines subsequent effector function of the antibody, including activation of complement (Kabat, E. A., Structural Concepts in Immunology and Immunochemistry, 2nd Ed., p. 413-436, Holt, Rinehart, Winston (1976)), and other cellular responses (Andrews, D. W., et al, Clinical Immunobiology, pp 1-18, W. B.
  • Light chains are classified as either ⁇ (kappa) or ⁇ (lambda). Each heavy chain class can be prepared with either kappa or lambda light chain. The light and heavy chains are covalently bonded to each other, and the "tail" portions of the two heavy chains are bonded to each other by covalent disulfide linkages when the immunoglobulins are generated either by hybridomas or by B cells.
  • variable region refers to the domains within each pair of light and heavy chains in an antibody that are involved directly in binding the antibody to the antigen.
  • Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains.
  • Each light chain has a variable domain (VL) at one end and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain.
  • CDR complementarity determining region
  • hypervariable region refers to one or more of the hyper-variable or complementarity determining regions (CDRs) found in the variable regions of light or heavy chains of an antibody (See Kabat, E. A. et al., Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., (1987)). These expressions include the hypervariable regions as defined by Kabat et al. ("Sequences of Proteins of Immunological Interest,” Kabat E., et al., US Dept. of Health and Human Services, 1983) or the hypervariable loops in 3- dimensional structures of antibodies (Chothia and Lesk, J Mol.
  • the CDRs in each chain are held in close proximity by framework regions and, with the CDRs from the other chain, contribute to the formation of the antigen binding site.
  • the CDRs there are select amino acids that have been described as the selectivity determining regions (SDRs) which represent the critical contact residues used by the CDR in the antibody-antigen interaction (Kashmiri, S., Methods, 36:25-34 (2005)).
  • framework region refers to one or more of the framework regions within the variable regions of the light and heavy chains of an antibody (See Kabat, E. A. et al., Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., (1987)). These expressions include those amino acid sequence regions interposed between the CDRs within the variable regions of the light and heavy chains of an antibody.
  • the present invention broadly contemplates the use of any anti-CGRP antibody or antibody fragment for the treatment or prevention of CGRP-associated diarrhea in any disease or condition resulting in increased levels of CGRP that are involved in diarrhea, and/or increased fluid or electrolyte excretion from the colon. Conditions and treatments resulting in increased CGRP which is associated with diarrhea are identified in this application.
  • the invention includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable light chain sequence comprising the sequence set forth below: QVLTQTASPVSAAVGSTVTINCQASQSVYDNNYLAWYQQKPGQPPKQLIYSTSTL ASGVSSRFKGSGSGTQFTLTISDLECADAATYYCLGSYDCSSGDCFVFGGGTEVVV KR (SEQ ID NO: 1).
  • the invention also includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a light chain sequence comprising the sequence set forth below: QVLTQTASPVSAAVGSTVTINCQASQSVYDNNYLAWYQQKPGQPPKQLIYSTSTL ASGVSSRFKGSGSGTQFTLTISDLECADAATYYCLGSYDCSSGDCFVFGGGTEVVV KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
  • the invention further includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable heavy chain sequence comprising the sequence set forth below: QSLEESGGRLVTPGTPLTLTCTVSGLDLSSYYMQWVRQAPGKGLEWIGVIGINDNT YYASWAKGRFTISRASSTTVDLKMTSLTTEDTATYFCARGDIWGPGTLVTVSS
  • the invention also includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a heavy chain sequence comprising the sequence set forth below: QSLEESGGRLVTPGTPLTLTCTVSGLDLSSYYMQWVRQAPGKGLEWIGVIGINDNT YYASWAKGRFTISRASSTTVDLKMTSLTTEDTATYFCARGDIWGPGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPE LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQ
  • the invention further contemplates antibodies for the treatment or prevention of CGRP-associated diarrhea comprising one or more of the polypeptide sequences of SEQ ID NO: 5; SEQ ID NO: 6; and SEQ ID NO: 7 which correspond to the complementarity- determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 1 or the light chain sequence of SEQ ID NO: 2, and/or one or more of the polypeptide sequences of SEQ ID NO: 8; SEQ ID NO: 9; and SEQ ID NO: 10 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 3 or the heavy chain sequence of SEQ ID NO: 4, or combinations of these polypeptide sequences.
  • the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 1 or SEQ ID NO: 2.
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 3 or SEQ ID NO: 4.
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 5; SEQ ID NO: 6; and SEQ ID NO: 7 which correspond to the complementarity- determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 1 or the light chain sequence of SEQ ID NO: 2.
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 8; SEQ ID NO: 9; and SEQ ID NO: 10 which correspond to the complementarity- determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 3 or the heavy chain sequence of SEQ ID NO: 4.
  • fragments of the antibodies having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 1; the variable heavy chain region of SEQ ID NO: 3; the complementarity- determining regions (SEQ ID NO: 5; SEQ ID NO: 6; and SEQ ID NO: 7) of the variable light chain region of SEQ ID NO: 1; and the complementarity-determining regions (SEQ ID NO: 8; SEQ ID NO: 9; and SEQ ID NO: 10) of the variable heavy chain region of SEQ ID NO: 3.
  • the chimeric anti- CGRP antibody for the treatment or prevention of CGRP-associated diarrhea is Abl, comprising, or alternatively consisting of, SEQ ID NO: 2 and SEQ ID NO: 4, and having at least one of the biological activities set forth herein.
  • antibody fragments for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • the Fab fragment includes the variable light chain sequence of SEQ ID NO: 1 and the variable heavy chain sequence of SEQ ID NO: 3.
  • This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 1 and/or SEQ ID NO: 3 in said Fab while retaining binding specificity for CGRP.
  • Fab fragments for the treatment or prevention of CGRP-associated diarrhea may be produced by enzymatic digestion (e.g., papain) of Abl .
  • anti-CGRP antibodies for the treatment or prevention of CGRP-associated diarrhea such as Abl or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable light chain sequence comprising the sequence set forth below: QVLTQSPSSLSASVGDRVTINCQASQSVYDNNYLAWYQQKPGKVPKQLIYSTSTL ASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGSYDCSSGDCFVFGGGTKVEIK
  • the invention also includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a light chain sequence comprising the sequence set forth below: QVLTQSPSSLSASVGDRVTINCQASQSVYDNNYLAWYQQKPGKVPKQLIYSTSTL ASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGSYDCSSGDCFVFGGGTKVEIK RT V AAP S VFIFPPSDEQLKS GT AS V VCLLNNF YPRE AKVQ WKVDN ALQ S GNS QE S VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
  • the invention further includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAVSGLDLSSYYMQWVRQAPGKGLEWVGVIGIN DNTYYASWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCARGDIWGQGTLVT VSS (SEQ ID NO: 13).
  • the invention also includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a heavy chain sequence comprising the sequence set forth below:
  • the invention further contemplates antibodies for the treatment or prevention of CGRP-associated diarrhea comprising one or more of the polypeptide sequences of SEQ ID NO: 15; SEQ ID NO: 16; and SEQ ID NO: 17 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 11 or the light chain sequence of SEQ ID NO: 12, and/or one or more of the polypeptide sequences of SEQ ID NO: 18; SEQ ID NO: 19; and SEQ ID NO: 20 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 13 or the heavy chain sequence of SEQ ID NO: 14, or combinations of these polypeptide sequences.
  • the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them
  • the invention also contemplates fragments of the antibody for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP.
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 11 or SEQ ID NO: 12.
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 13 or SEQ ID NO: 14.
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 15; SEQ ID NO: 16; and SEQ ID NO: 17 which correspond to the complementarity- determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 11 or the light chain sequence of SEQ ID NO: 12.
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 18; SEQ ID NO: 19; and SEQ ID NO: 20 which correspond to the complementarity- determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 13 or the heavy chain sequence of SEQ ID NO: 14.
  • fragments of the antibodies having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 11 ; the variable heavy chain region of SEQ ID NO: 13; the complementarity- determining regions (SEQ ID NO: 15; SEQ ID NO: 16; and SEQ ID NO: 17) of the variable light chain region of SEQ ID NO: 11; and the complementarity-determining regions (SEQ ID NO: 18; SEQ ID NO: 19; and SEQ ID NO: 20) of the variable heavy chain region of SEQ ID NO: 13.
  • the humanized anti- CGRP antibody for the treatment or prevention of CGRP-associated diarrhea is Ab2, comprising, or alternatively consisting of, SEQ ID NO: 12 and SEQ ID NO: 14, and having at least one of the biological activities set forth herein.
  • antibody fragments for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • the Fab fragment includes the variable light chain sequence of SEQ ID NO: 11 and the variable heavy chain sequence of SEQ ID NO: 13.
  • This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 11 and/or SEQ ID NO: 13 in said Fab while retaining binding specificity for CGRP.
  • Fab fragments for the treatment or prevention of CGRP-associated diarrhea may be produced by enzymatic digestion (e.g., papain) of Ab2.
  • anti-CGRP antibodies for the treatment or prevention of CGRP-associated diarrhea such as Ab2 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable light chain sequence comprising the sequence set forth below: QVLTQSPSSLSASVGDRVTINCQASQSVYDNNYLAWYQQKPGKVPKQLIYSTSTL ASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGSYDCSSGDCFVFGGGTKVEIK
  • the invention also includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a light chain sequence comprising the sequence set forth below: QVLTQSPSSLSASVGDRVTINCQASQSVYDNNYLAWYQQKPGKVPKQLIYSTSTL ASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGSYDCSSGDCFVFGGGTKVEIK RT V AAP S VFIFPPSDEQLKS GT AS V VCLLNNF YPRE AKVQ WKVDN ALQ S GNS QE S VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
  • the invention further includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAVSGLDLSSYYMQWVRQAPGKGLEWVGVIGIN DNTYYASWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCARGDIWGQGTLVT VSS (SEQ ID NO: 23).
  • the invention also includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAVSGLDLSSYYMQWVRQAPGKGLEWVGVIGIN DNTYYASWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCARGDIWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF P AVLQ S S GL YSL S SWT VP S S SLGTQT YI CN VNHKP SNTKVD ARVEPKS CDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS
  • the invention further contemplates antibodies for the treatment or prevention of CGRP-associated diarrhea comprising one or more of the polypeptide sequences of SEQ ID NO: 25; SEQ ID NO: 26; and SEQ ID NO: 27 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 21 or the light chain sequence of SEQ ID NO: 22, and/or one or more of the polypeptide sequences of SEQ ID NO: 28; SEQ ID NO: 29; and SEQ ID NO: 30 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 23 or the heavy chain sequence of SEQ ID NO: 24, or combinations of these polypeptide sequences.
  • SEQ ID NO: 25; SEQ ID NO: 26; and SEQ ID NO: 27 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 21 or the light chain sequence of S
  • the antibodies of the invention or fragments thereof for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.
  • the invention also contemplates fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea.
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 21 or SEQ ID NO: 22.
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 23 or SEQ ID NO: 24.
  • fragments of the antibody having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 25; SEQ ID NO: 26; and SEQ ID NO: 27 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 21 or the light chain sequence of SEQ ID NO: 22.
  • CDRs complementarity-determining regions
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 28; SEQ ID NO: 29; and SEQ ID NO: 30 which correspond to the complementarity- determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 23 or the heavy chain sequence of SEQ ID NO: 24.
  • CDRs complementarity- determining regions
  • the invention also contemplates antibody fragments for the treatment or prevention of CGRP-associated diarrhea which include one or more of the antibody fragments described herein.
  • fragments of the antibodies having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 21; the variable heavy chain region of SEQ ID NO: 23; the complementarity-determining regions (SEQ ID NO: 25; SEQ ID NO: 26; and SEQ ID NO: 27) of the variable light chain region of SEQ ID NO: 21; and the complementarity- determining regions (SEQ ID NO: 28; SEQ ID NO: 29; and SEQ ID NO: 30) of the variable heavy chain region of SEQ ID NO: 23.
  • the chimeric anti-CGRP antibody for the treatment or prevention of CGRP-associated diarrhea is Ab3, comprising, or alternatively consisting of, SEQ ID NO: 22 and SEQ ID NO: 24, and having at least one of the biological activities set forth herein.
  • antibody fragments for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • Fab fragment antigen binding
  • the Fab fragment includes the variable light chain sequence of SEQ ID NO: 21 and the variable heavy chain sequence of SEQ ID NO: 23.
  • This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 21 and/or SEQ ID NO: 23 in said Fab while retaining binding specificity for CGRP.
  • Fab fragments for the treatment or prevention of CGRP-associated diarrhea may be produced by enzymatic digestion (e.g., papain) of Ab3.
  • anti-CGRP antibodies for the treatment or prevention of CGRP-associated diarrhea such as Ab3 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable light chain sequence comprising the sequence set forth below: QVLTQTPSPVSAAVGSTVTINCQASQSVYHNTYLAWYQQKPGQPPKQLIYDASTL ASGVPSRFSGSGSGTQFTLTISGVQCNDAAAYYCLGSYDCTNGDCFVFGGGTEVV VKR (SEQ ID NO: 31).
  • the invention also includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a light chain sequence comprising the sequence set forth below: QVLTQTPSPVSAAVGSTVTINCQASQSVYHNTYLAWYQQKPGQPPKQLIYDASTL ASGVPSRFSGSGSGTQFTLTISGVQCNDAAAYYCLGSYDCTNGDCFVFGGGTEVV VKRT V AAP S VFIFPP SDEQLKS GT AS V VCLLNNF YPRE AKVQ WKVDN ALQ S GNS Q ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
  • the invention further includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable heavy chain sequence comprising the sequence set forth below: QSLEESGGRLVTPGTPLTLTCSVSGIDLSGYYMNWVRQAPGKGLEWIGVIGINGAT YYASWAKGRFTISKTSSTTVDLKMTSLTTEDTATYFCARGDIWGPGTLVTVSS (SEQ ID NO: 33).
  • the invention also includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a heavy chain sequence comprising the sequence set forth below: QSLEESGGRLVTPGTPLTLTCSVSGIDLSGYYMNWVRQAPGKGLEWIGVIGINGAT YYASWAKGRFTISKTSSTTVDLKMTSLTTEDTATYFCARGDIWGPGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPE LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKN
  • the invention further contemplates antibodies for the treatment or prevention of CGRP-associated diarrhea comprising one or more of the polypeptide sequences of SEQ ID NO: 35; SEQ ID NO: 36; and SEQ ID NO: 37 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 31 or the light chain sequence of SEQ ID NO: 32, and/or one or more of the polypeptide sequences of SEQ ID NO: 38; SEQ ID NO: 39; and SEQ ID NO: 40 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 33 or the heavy chain sequence of SEQ ID NO: 34, or combinations of these polypeptide sequences.
  • the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all
  • the invention also contemplates fragments of the antibody for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP.
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 31 or SEQ ID NO: 32.
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 33 or SEQ ID NO: 34.
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 35; SEQ ID NO: 36; and SEQ ID NO: 37 which correspond to the complementarity- determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 31 or the light chain sequence of SEQ ID NO: 32.
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 38; SEQ ID NO: 39; and SEQ ID NO: 40 which correspond to the complementarity- determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 33 or the heavy chain sequence of SEQ ID NO: 34.
  • the invention also contemplates antibody fragments for the treatment or prevention of CGRP-associated diarrhea which include one or more of the antibody fragments described herein.
  • fragments of the antibodies having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 31; the variable heavy chain region of SEQ ID NO: 33; the complementarity-determining regions (SEQ ID NO: 35; SEQ ID NO: 36; and SEQ ID NO: 37) of the variable light chain region of SEQ ID NO: 31; and the complementarity- determining regions (SEQ ID NO: 38; SEQ ID NO: 39; and SEQ ID NO: 40) of the variable heavy chain region of SEQ ID NO: 33.
  • the humanized anti- CGRP antibody for the treatment or prevention of CGRP-associated diarrhea is Ab4, comprising, or alternatively consisting of, SEQ ID NO: 32 and SEQ ID NO: 34, and having at least one of the biological activities set forth herein.
  • antibody fragments for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • the Fab fragment includes the variable light chain sequence of SEQ ID NO: 31 and the variable heavy chain sequence of SEQ ID NO: 33.
  • This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 31 and/or SEQ ID NO: 33 in said Fab while retaining binding specificity for CGRP.
  • Fab fragments for the treatment or prevention of CGRP-associated diarrhea may be produced by enzymatic digestion (e.g., papain) of Ab4.
  • anti-CGRP antibodies for the treatment or prevention of CGRP-associated diarrhea such as Ab4 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable light chain sequence comprising the sequence set forth below: QVLTQSPSSLSASVGDRVTINCQASQSVYHNTYLAWYQQKPGKVPKQLIYDASTL ASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGSYDCTNGDCFVFGGGTKVEIK
  • the invention also includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a light chain sequence comprising the sequence set forth below: QVLTQSPSSLSASVGDRVTINCQASQSVYHNTYLAWYQQKPGKVPKQLIYDASTL ASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGSYDCTNGDCFVFGGGTKVEIK RT V AAP S VFIFPPSDEQLKS GT AS V VCLLNNF YPRE AKVQ WKVDN ALQ S GNS QE S VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 42).
  • the invention further includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAVSGIDLSGYYMNWVRQAPGKGLEWVGVIGIN GATYYASWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCARGDIWGQGTLVT VSS (SEQ ID NO: 43).
  • the invention also includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAVSGIDLSGYYMNWVRQAPGKGLEWVGVIGIN GATYYASWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCARGDIWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF P AVLQ S S GL YSL S SWT VP S S SLGTQT YI CN VNHKP SNTKVDKRVEPKS CDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS
  • the invention further contemplates antibodies for the treatment or prevention of CGRP-associated diarrhea comprising one or more of the polypeptide sequences of SEQ ID NO: 45; SEQ ID NO: 46; and SEQ ID NO: 47 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 41 or the light chain sequence of SEQ ID NO: 42, and/or one or more of the polypeptide sequences of SEQ ID NO: 48; SEQ ID NO: 49; and SEQ ID NO: 50 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 43 or the heavy chain sequence of SEQ ID NO: 44, or combinations of these polypeptide sequences.
  • the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including
  • the invention also contemplates fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea.
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 41 or SEQ ID NO: 42.
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 43 or SEQ ID NO: 44.
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 45; SEQ ID NO: 46; and SEQ ID NO: 47 which correspond to the complementarity- determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 41 or the light chain sequence of SEQ ID NO: 42.
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 48; SEQ ID NO: 49; and SEQ ID NO: 50 which correspond to the complementarity- determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 43 or the heavy chain sequence of SEQ ID NO: 44.
  • CDRs complementarity- determining regions
  • fragments of the antibodies having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 41; the variable heavy chain region of SEQ ID NO: 43; the complementarity-determining regions (SEQ ID NO: 45; SEQ ID NO: 46; and SEQ ID NO: 47) of the variable light chain region of SEQ ID NO: 41; and the complementarity- determining regions (SEQ ID NO: 48; SEQ ID NO: 49; and SEQ ID NO: 50) of the variable heavy chain region of SEQ ID NO: 43.
  • the chimeric anti-CGRP antibody for the treatment or prevention of CGRP-associated diarrhea is Ab5, comprising, or alternatively consisting of, SEQ ID NO: 42 and SEQ ID NO: 44, and having at least one of the biological activities set forth herein.
  • antibody fragments for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • Fab fragment antigen binding
  • the Fab fragment includes the variable light chain sequence of SEQ ID NO: 41 and the variable heavy chain sequence of SEQ ID NO: 43.
  • This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 41 and/or SEQ ID NO: 43 in said Fab while retaining binding specificity for CGRP.
  • Fab fragments for the treatment or prevention of CGRP-associated diarrhea may be produced by enzymatic digestion (e.g., papain) of Ab5.
  • anti-CGRP antibodies such as Ab5 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable light chain sequence comprising the sequence set forth below: QVLTQSPSSLSASVGDRVTINCQASQSVYHNTYLAWYQQKPGKVPKQLIYDASTL ASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGSYDCTNGDCFVFGGGTKVEIK
  • the invention also includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a light chain sequence comprising the sequence set forth below: QVLTQSPSSLSASVGDRVTINCQASQSVYHNTYLAWYQQKPGKVPKQLIYDASTL ASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGSYDCTNGDCFVFGGGTKVEIK RT V AAP S VFIFPPSDEQLKS GT AS V VCLLNNF YPRE AKVQ WKVDN ALQ S GNS QE S VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
  • the invention further includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAVSGIDLSGYYMNWVRQAPGKGLEWVGVIGIN GATYYASWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCARGDIWGQGTLVT VSS (SEQ ID NO: 53).
  • the invention also includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAVSGIDLSGYYMNWVRQAPGKGLEWVGVIGIN GATYYASWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCARGDIWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF P AVLQ S S GL YSL S SWT VP S S SLGTQT YI CN VNHKP SNTKVD ARVEPKS CDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS
  • the invention further contemplates antibodies for the treatment or prevention of CGRP-associated diarrhea comprising one or more of the polypeptide sequences of SEQ ID NO: 55; SEQ ID NO: 56; and SEQ ID NO: 57 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 51 or the light chain sequence of SEQ ID NO: 52, and/or one or more of the polypeptide sequences of SEQ ID NO: 58; SEQ ID NO: 59; and SEQ ID NO: 60 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 53 or the heavy chain sequence of SEQ ID NO: 54, or combinations of these polypeptide sequences.
  • the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth
  • the invention also contemplates fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea.
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 51 or SEQ ID NO: 52.
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 53 or SEQ ID NO: 54.
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 55; SEQ ID NO: 56; and SEQ ID NO: 57 which correspond to the complementarity- determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 51 or the light chain sequence of SEQ ID NO: 52.
  • CDRs complementarity- determining regions
  • fragments of the antibody for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 58; SEQ ID NO: 59; and SEQ ID NO: 60 which correspond to the complementarity- determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 53 or the heavy chain sequence of SEQ ID NO: 54.
  • the invention also contemplates antibody fragments for the treatment or prevention of CGRP-associated diarrhea which include one or more of the antibody fragments described herein.
  • fragments of the antibodies having binding specificity to CGRP for the treatment or prevention of CGRP- associated diarrhea comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 51; the variable heavy chain region of SEQ ID NO: 53; the complementarity-determining regions (SEQ ID NO: 55; SEQ ID NO: 56; and SEQ ID NO: 57) of the variable light chain region of SEQ ID NO: 51; and the complementarity-determining regions (SEQ ID NO: 58; SEQ ID NO: 59; and SEQ ID NO: 60) of the variable heavy chain region of SEQ ID NO: 53.
  • the humanized anti- CGRP antibody for the treatment or prevention of CGRP-associated diarrhea is Ab6, comprising, or alternatively consisting of, SEQ ID NO: 52 and SEQ ID NO: 54, and having at least one of the biological activities set forth herein.
  • antibody fragments for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • Fab fragment antigen binding
  • the Fab fragment includes the variable light chain sequence of SEQ ID NO: 51 and the variable heavy chain sequence of SEQ ID NO: 53.
  • This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 51 and/or SEQ ID NO: 53 in said Fab while retaining binding specificity for CGRP.
  • Fab fragments for the treatment or prevention of CGRP-associated diarrhea may be produced by enzymatic digestion (e.g., papain) of Ab6.
  • anti-CGRP antibodies for the treatment or prevention of CGRP-associated diarrhea such as Ab6 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable light chain sequence comprising the sequence set forth below: QVLTQTASPVSAAVGSTVTINCQASQSVYNYNYLAWYQQKPGQPPKQLIYSTSTL ASGVSSRFKGSGSGTQFTLTISDVQCDDAATYYCLGSYDCSTGDCFVFGGGTEVV VKR (SEQ ID NO: 61).
  • the invention also includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a light chain sequence comprising the sequence set forth below: QVLTQTASPVSAAVGSTVTINCQASQSVYNYNYLAWYQQKPGQPPKQLIYSTSTL ASGVSSRFKGSGSGTQFTLTISDVQCDDAATYYCLGSYDCSTGDCFVFGGGTEVV VKRT V AAP S VFIFPP SDEQLKS GT AS V VCLLNNF YPRE AKVQ WKVDN ALQ S GNS Q ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
  • the invention further includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable heavy chain sequence comprising the sequence set forth below: QEQLKESGGRLVTPGTSLTLTCTVSGIDLSNHYMQWVRQAPGKGLEWIGVVGING RTYYASWAKGRFTISRTSSTTVDLKMTRLTTEDTATYFCARGDIWGPGTLVTVSS
  • the invention also includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a heavy chain sequence comprising the sequence set forth below: QEQLKESGGRLVTPGTSLTLTCTVSGIDLSNHYMQWVRQAPGKGLEWIGVVGING RTYYASWAKGRFTISRTSSTTVDLKMTRLTTEDTATYFCARGDIWGPGTLVTVSSA STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPSREEMTKNQVSLTC
  • the invention further contemplates antibodies for the treatment or prevention of CGRP-associated diarrhea comprising one or more of the polypeptide sequences of SEQ ID NO: 65; SEQ ID NO: 66; and SEQ ID NO: 67 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 61 or the light chain sequence of SEQ ID NO: 62, and/or one or more of the polypeptide sequences of SEQ ID NO: 68; SEQ ID NO: 69; and SEQ ID NO: 70 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 63 or the heavy chain sequence of SEQ ID NO: 64, or combinations of these polypeptide sequences.
  • the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 61 or SEQ ID NO: 62. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 63 or SEQ ID NO: 64.
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 65; SEQ ID NO: 66; and SEQ ID NO: 67 which correspond to the complementarity- determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 61 or the light chain sequence of SEQ ID NO: 62.
  • CDRs complementarity- determining regions
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 68; SEQ ID NO: 69; and SEQ ID NO: 70 which correspond to the complementarity- determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 63 or the heavy chain sequence of SEQ ID NO: 64.
  • CDRs complementarity- determining regions
  • fragments of the antibodies having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 61; the variable heavy chain region of SEQ ID NO: 63; the complementarity-determining regions (SEQ ID NO: 65; SEQ ID NO: 66; and SEQ ID NO: 67) of the variable light chain region of SEQ ID NO: 61; and the complementarity- determining regions (SEQ ID NO: 68; SEQ ID NO: 69; and SEQ ID NO: 70) of the variable heavy chain region of SEQ ID NO: 63.
  • the chimeric anti-CGRP antibody for the treatment or prevention of CGRP-associated diarrhea is Ab7, comprising, or alternatively consisting of, SEQ ID NO: 62 and SEQ ID NO: 64, and having at least one of the biological activities set forth herein.
  • antibody fragments for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • the Fab fragment includes the variable light chain sequence of SEQ ID NO: 61 and the variable heavy chain sequence of SEQ ID NO: 63.
  • This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 61 and/or SEQ ID NO: 63 in said Fab while retaining binding specificity for CGRP.
  • Fab fragments for the treatment or prevention of CGRP-associated diarrhea may be produced by enzymatic digestion (e.g., papain) of Ab7.
  • anti-CGRP antibodies such as Ab7 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention includes chimeric or humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable light chain sequence comprising the sequence set forth below:
  • the invention also includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a light chain sequence comprising the sequence set forth below: QVLTQSPSSLSASVGDRVTINCQASQSVYNYNYLAWYQQKPGKVPKQLIYSTSTL ASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGSYDCSTGDCFVFGGGTKVEIK RT V AAP S VFIFPPSDEQLKS GT AS V VCLLNNF YPRE AKVQ WKVDN ALQ S GNS QE S VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
  • the invention further includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAVSGIDLSNHYMQWVRQAPGKGLEWVGVVGIN GRTYYASWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCARGDIWGQGTLVT VSS (SEQ ID NO: 73).
  • the invention also includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAVSGIDLSNHYMQWVRQAPGKGLEWVGVVGIN GRTYYASWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCARGDIWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF P AVLQ S S GL YSL S SWT VP S S SLGTQT YI CN VNHKP SNTKVDKRVEPKS CDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT
  • the invention further contemplates antibodies for the treatment or prevention of CGRP-associated diarrhea comprising one or more of the polypeptide sequences of SEQ ID NO: 75; SEQ ID NO: 76; and SEQ ID NO: 77 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 71 or the light chain sequence of SEQ ID NO: 72, and/or one or more of the polypeptide sequences of SEQ ID NO: 78; SEQ ID NO: 79; and SEQ ID NO: 80 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 73 or the heavy chain sequence of SEQ ID NO: 74, or combinations of these polypeptide sequences.
  • the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain
  • the invention also contemplates fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea.
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 71 or SEQ ID NO: 72.
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 73 or SEQ ID NO: 74.
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 75; SEQ ID NO: 76; and SEQ ID NO: 77 which correspond to the complementarity- determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 71 or the light chain sequence of SEQ ID NO: 72.
  • CDRs complementarity- determining regions
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 78; SEQ ID NO: 79; and SEQ ID NO: 80 which correspond to the complementarity- determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 73 or the heavy chain sequence of SEQ ID NO: 74.
  • CDRs complementarity- determining regions
  • the invention also contemplates antibody fragments for the treatment or prevention of CGRP-associated diarrhea which include one or more of the antibody fragments described herein.
  • fragments of the antibodies having binding specificity to CGRP for the treatment or prevention of CGRP- associated diarrhea comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 71; the variable heavy chain region of SEQ ID NO: 73; the complementarity-determining regions (SEQ ID NO: 75; SEQ ID NO: 76; and SEQ ID NO: 77) of the variable light chain region of SEQ ID NO: 71; and the complementarity-determining regions (SEQ ID NO: 78; SEQ ID NO: 79; and SEQ ID NO: 80) of the variable heavy chain region of SEQ ID NO: 73.
  • the humanized anti- CGRP antibody for the treatment or prevention of CGRP-associated diarrhea is Ab8, comprising, or alternatively consisting of, SEQ ID NO: 72 and SEQ ID NO: 74, and having at least one of the biological activities set forth herein.
  • antibody fragments for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • the Fab fragment includes the variable light chain sequence of SEQ ID NO: 71 and the variable heavy chain sequence of SEQ ID NO: 73.
  • This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 71 and/or SEQ ID NO: 73 in said Fab while retaining binding specificity for CGRP.
  • Fab fragments for the treatment or prevention of CGRP-associated diarrhea may be produced by enzymatic digestion (e.g., papain) of Ab8.
  • anti-CGRP antibodies for the treatment or prevention of CGRP-associated diarrhea such as Ab8 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable light chain sequence comprising the sequence set forth below: QVLTQTPSPVSAAVGSTVTINCQASQNVYNNNYLAWYQQKPGQPPKQLIYSTSTL ASGVSSRFRGSGSGTQFTLTISDVQCDDAATYYCLGSYDCSRGDCFVFGGGTEVV VKR (SEQ ID NO: 81).
  • the invention also includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a light chain sequence comprising the sequence set forth below: QVLTQTPSPVSAAVGSTVTINCQASQNVYNNNYLAWYQQKPGQPPKQLIYSTSTL ASGVSSRFRGSGSGTQFTLTISDVQCDDAATYYCLGSYDCSRGDCFVFGGGTEVV VKRT V AAP S VFIFPP SDEQLKS GT AS V VCLLNNF YPRE AKVQ WKVDN ALQ S GNS Q ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
  • the invention further includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable heavy chain sequence comprising the sequence set forth below: QSLEESGGRLVTPGTPLTLTCTVSGIGLSSYYMQWVRQSPGRGLEWIGVIGSDGKT YYATWAKGRFTISKTSSTTVDLRMASLTTEDTATYFCTRGDIWGPGTLVTVSS (SEQ ID NO: 83).
  • the invention also includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a heavy chain sequence comprising the sequence set forth below: QSLEESGGRLVTPGTPLTLTCTVSGIGLSSYYMQWVRQSPGRGLEWIGVIGSDGKT YYATWAKGRFTISKTSSTTVDLRMASLTTEDTATYFCTRGDIWGPGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPE LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEM
  • the invention further contemplates antibodies for the treatment or prevention of CGRP-associated diarrhea comprising one or more of the polypeptide sequences of SEQ ID NO: 85; SEQ ID NO: 86; and SEQ ID NO: 87 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 81 or the light chain sequence of SEQ ID NO: 82, and/or one or more of the polypeptide sequences of SEQ ID NO: 88; SEQ ID NO: 89; and SEQ ID NO: 90 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 83 or the heavy chain sequence of SEQ ID NO: 84, or combinations of these polypeptide sequences.
  • SEQ ID NO: 85 SEQ ID NO: 86; and SEQ ID NO: 87 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ
  • the antibodies of the invention or fragments thereof for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.
  • the invention also contemplates fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea.
  • antibody fragments of the invention for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 81 or SEQ ID NO: 82.
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 83 or SEQ ID NO: 84.
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 85; SEQ ID NO: 86; and SEQ ID NO: 87 which correspond to the complementarity- determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 81 or the light chain sequence of SEQ ID NO: 82.
  • CDRs complementarity- determining regions
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 88; SEQ ID NO: 89; and SEQ ID NO: 90 which correspond to the complementarity- determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 83 or the heavy chain sequence of SEQ ID NO: 84.
  • CDRs complementarity- determining regions
  • the invention also contemplates antibody fragments for the treatment or prevention of CGRP-associated diarrhea which include one or more of the antibody fragments described herein.
  • fragments of the antibodies having binding specificity to CGRP for the treatment or prevention of CGRP- associated diarrhea comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 81; the variable heavy chain region of SEQ ID NO: 83; the complementarity-determining regions (SEQ ID NO: 85; SEQ ID NO: 86; and SEQ ID NO: 87) of the variable light chain region of SEQ ID NO: 81; and the complementarity-determining regions (SEQ ID NO: 88; SEQ ID NO: 89; and SEQ ID NO: 90) of the variable heavy chain region of SEQ ID NO: 83.
  • the chimeric anti-CGRP antibody for the treatment or prevention of CGRP-associated diarrhea is Ab9, comprising, or alternatively consisting of, SEQ ID NO: 82 and SEQ ID NO: 84, and having at least one of the biological activities set forth herein.
  • antibody fragments for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • Fab fragment antigen binding
  • the Fab fragment for the treatment or prevention of CGRP-associated diarrhea includes the variable light chain sequence of SEQ ID NO: 81 and the variable heavy chain sequence of SEQ ID NO: 83.
  • This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 81 and/or SEQ ID NO: 83 in said Fab while retaining binding specificity for CGRP.
  • Fab fragments for the treatment or prevention of CGRP-associated diarrhea may be produced by enzymatic digestion (e.g., papain) of Ab9.
  • anti-CGRP antibodies for the treatment or prevention of CGRP-associated diarrhea such as Ab9 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable light chain sequence comprising the sequence set forth below: QVLTQSPSSLSASVGDRVTINCQASQNVYNNNYLAWYQQKPGKVPKQLIYSTSTL ASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGSYDCSRGDCFVFGGGTKVEIK
  • the invention also includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a light chain sequence comprising the sequence set forth below: QVLTQSPSSLSASVGDRVTINCQASQNVYNNNYLAWYQQKPGKVPKQLIYSTSTL ASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGSYDCSRGDCFVFGGGTKVEIK RT V AAP S VFIFPPSDEQLKS GT AS V VCLLNNF YPRE AKVQ WKVDN ALQ S GNS QE S VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
  • the invention further includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAVSGIGLSSYYMQWVRQAPGKGLEWVGVIGSD GKTYYATWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCTRGDIWGQGTLVT VSS (SEQ ID NO: 93).
  • the invention also includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAVSGIGLSSYYMQWVRQAPGKGLEWVGVIGSD GKTYYATWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCTRGDIWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF P AVLQ S S GL YSL S SWT VP S S SLGTQT YI CN VNHKP SNTKVDKRVEPKS CDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP
  • the invention further contemplates antibodies for the treatment or prevention of CGRP-associated diarrhea comprising one or more of the polypeptide sequences of SEQ ID NO: 95; SEQ ID NO: 96; and SEQ ID NO: 97 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 91 or the light chain sequence of SEQ ID NO: 92, and/or one or more of the polypeptide sequences of SEQ ID NO: 98; SEQ ID NO: 99; and SEQ ID NO: 100 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 93 or the heavy chain sequence of SEQ ID NO: 94, or combinations of these polypeptide sequences.
  • the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequence
  • the invention also contemplates fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea.
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 91 or SEQ ID NO: 92.
  • antibody fragments of the invention for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 93 or SEQ ID NO: 94.
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 95; SEQ ID NO: 96; and SEQ ID NO: 97 which correspond to the complementarity- determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 91 or the light chain sequence of SEQ ID NO: 92.
  • CDRs complementarity- determining regions
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 98; SEQ ID NO: 99; and SEQ ID NO: 100 which correspond to the complementarity- determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 93 or the heavy chain sequence of SEQ ID NO: 94.
  • the invention also contemplates antibody fragments for the treatment or prevention of CGRP-associated diarrhea which include one or more of the antibody fragments described herein.
  • fragments of the antibodies having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 91; the variable heavy chain region of SEQ ID NO: 93; the complementarity-determining regions (SEQ ID NO: 95; SEQ ID NO: 96; and SEQ ID NO: 97) of the variable light chain region of SEQ ID NO: 91; and the complementarity- determining regions (SEQ ID NO: 98; SEQ ID NO: 99; and SEQ ID NO: 100) of the variable heavy chain region of SEQ ID NO: 93.
  • the humanized anti- CGRP antibody for the treatment or prevention of CGRP-associated diarrhea is AblO, comprising, or alternatively consisting of, SEQ ID NO: 92 and SEQ ID NO: 94, and having at least one of the biological activities set forth herein.
  • antibody fragments for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • Fab fragment antigen binding
  • the Fab fragment for the treatment or prevention of CGRP-associated diarrhea includes the variable light chain sequence of SEQ ID NO: 91 and the variable heavy chain sequence of SEQ ID NO: 93.
  • This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 91 and/or SEQ ID NO: 93 in said Fab while retaining binding specificity for CGRP.
  • Fab fragments for the treatment or prevention of CGRP-associated diarrhea may be produced by enzymatic digestion (e.g., papain) of AblO.
  • anti-CGRP antibodies such as AblO or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable light chain sequence comprising the sequence set forth below: QVLTQTASPVSPAVGSTVTINCRASQSVYYNNYLAWYQQKPGQPPKQLIYSTSTLA SGVSSRFKGSGSGTQFTLTISDVQCDDAATYYCLGSYDCSNGDCFVFGGGTEVVV KR (SEQ ID NO: 101).
  • the invention also includes chimeric antibodies having binding specificity to
  • the invention further includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable heavy chain sequence comprising the sequence set forth below: QSLEESGGRLVTPGGSLTLTCTVSGIDVTNYYMQWVRQAPGKGLEWIGVIGVNGK RYYASWAKGRFTISKTSSTTVDLKMTSLTTEDTATYFCARGDIWGPGTLVTVSS
  • the invention also includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a heavy chain sequence comprising the sequence set forth below: QSLEESGGRLVTPGGSLTLTCTVSGIDVTNYYMQWVRQAPGKGLEWIGVIGVNGK RYYASWAKGRFTISKTSSTTVDLKMTSLTTEDTATYFCARGDIWGPGTLVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAP ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSREEMTKNQVSL
  • the invention further contemplates antibodies for the treatment or prevention of CGRP-associated diarrhea comprising one or more of the polypeptide sequences of SEQ ID NO: 105; SEQ ID NO: 106; and SEQ ID NO: 107 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 101 or the light chain sequence of SEQ ID NO: 102, and/or one or more of the polypeptide sequences of SEQ ID NO: 108; SEQ ID NO: 109; and SEQ ID NO: 110 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 103 or the heavy chain sequence of SEQ ID NO: 104, or combinations of these polypeptide sequences.
  • the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 101 or SEQ ID NO: 102. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 103 or SEQ ID NO: 104.
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 105; SEQ ID NO: 106; and SEQ ID NO: 107 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 101 or the light chain sequence of SEQ ID NO: 102.
  • CDRs complementarity-determining regions
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 108; SEQ ID NO: 109; and SEQ ID NO: 110 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 103 or the heavy chain sequence of SEQ ID NO: 104.
  • CDRs complementarity-determining regions
  • the invention also contemplates antibody fragments for the treatment or prevention of CGRP-associated diarrhea which include one or more of the antibody fragments described herein.
  • fragments of the antibodies having binding specificity to CGRP for the treatment or prevention of CGRP- associated diarrhea comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 101; the variable heavy chain region of SEQ ID NO: 103; the complementarity- determining regions (SEQ ID NO: 105; SEQ ID NO: 106; and SEQ ID NO: 107) of the variable light chain region of SEQ ID NO: 101; and the complementarity-determining regions (SEQ ID NO: 108; SEQ ID NO: 109; and SEQ ID NO: 110) of the variable heavy chain region of SEQ ID NO: 103.
  • the chimeric anti-CGRP antibody for the treatment or prevention of CGRP-associated diarrhea is Abl 1, comprising, or alternatively consisting of, SEQ ID NO: 102 and SEQ ID NO: 104, and having at least one of the biological activities set forth herein.
  • antibody fragments for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • Fab fragment antigen binding
  • the Fab fragment for the treatment or prevention of CGRP-associated diarrhea includes the variable light chain sequence of SEQ ID NO: 101 and the variable heavy chain sequence of SEQ ID NO: 103.
  • This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 101 and/or SEQ ID NO: 103 in said Fab while retaining binding specificity for CGRP.
  • Fab fragments for the treatment or prevention of CGRP-associated diarrhea may be produced by enzymatic digestion (e.g., papain) of AM I .
  • anti-CGRP antibodies such as Abl l or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable light chain sequence comprising the sequence set forth below: QVLTQSPSSLSASVGDRVTINCRASQSVYYNNYLAWYQQKPGKVPKQLIYSTSTL ASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGSYDCSNGDCFVFGGGTKVEIK
  • the invention also includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a light chain sequence comprising the sequence set forth below: QVLTQSPSSLSASVGDRVTINCRASQSVYYNNYLAWYQQKPGKVPKQLIYSTSTL ASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGSYDCSNGDCFVFGGGTKVEIK RT V AAP S VFIFPPSDEQLKS GT AS V VCLLNNF YPRE AKVQ WKVDN ALQ S GNS QE S VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
  • the invention further includes humanized antibodies having binding specificity to CGRP and possessing a variable heavy chain sequence comprising the sequence set forth below:
  • the invention also includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAVSGIDVTNYYMQWVRQAPGKGLEWVGVIGVN GKRYYASWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCARGDIWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF P AVLQ S S GL YSL S SWT VP S S SLGTQT YI CN VNHKP SNTKVDKRVEPKS CDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE
  • the invention further contemplates antibodies for the treatment or prevention of CGRP-associated diarrhea comprising one or more of the polypeptide sequences of SEQ ID NO: 115; SEQ ID NO: 116; and SEQ ID NO: 117 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 1 11 or the light chain sequence of SEQ ID NO: 112, and/or one or more of the polypeptide sequences of SEQ ID NO: 118; SEQ ID NO: 119; and SEQ ID NO: 120 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 113 or the heavy chain sequence of SEQ ID NO: 114, or combinations of these polypeptide sequences.
  • CDRs complementarity-determining regions
  • the antibodies of the invention or fragments thereof for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.
  • the invention also contemplates fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea.
  • antibody fragments of the invention for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 111 or SEQ ID NO: 112.
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 113 or SEQ ID NO: 114.
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 115; SEQ ID NO: 116; and SEQ ID NO: 117 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 111 or the light chain sequence of SEQ ID NO: 112.
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 118; SEQ ID NO: 119; and SEQ ID NO: 120 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 113 or the heavy chain sequence of SEQ ID NO: 114.
  • CDRs complementarity-determining regions
  • the invention also contemplates antibody fragments for the treatment or prevention of CGRP-associated diarrhea which include one or more of the antibody fragments described herein.
  • fragments of the antibodies having binding specificity to CGRP for the treatment or prevention of CGRP- associated diarrhea comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 111; the variable heavy chain region of SEQ ID NO: 113; the complementarity- determining regions (SEQ ID NO: 115; SEQ ID NO: 116; and SEQ ID NO: 117) of the variable light chain region of SEQ ID NO: 111; and the complementarity-determining regions (SEQ ID NO: 118; SEQ ID NO: 119; and SEQ ID NO: 120) of the variable heavy chain region of SEQ ID NO: 113.
  • the humanized anti- CGRP antibody for the treatment or prevention of CGRP-associated diarrhea is Abl2, comprising, or alternatively consisting of, SEQ ID NO: 112 and SEQ ID NO: 114, and having at least one of the biological activities set forth herein.
  • antibody fragments for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • Fab fragment antigen binding
  • the Fab fragment for the treatment or prevention of CGRP-associated diarrhea includes the variable light chain sequence of SEQ ID NO: 111 and the variable heavy chain sequence of SEQ ID NO: 113.
  • This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 111 and/or SEQ ID NO: 113 in said Fab while retaining binding specificity for CGRP.
  • Fab fragments for the treatment or prevention of CGRP-associated diarrhea may be produced by enzymatic digestion (e.g., papain) of Abl2.
  • anti-CGRP antibodies for the treatment or prevention of CGRP-associated diarrhea such as Abl2 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable light chain sequence comprising the sequence set forth below: AIVMTQTPSSKSVPVGDTVTINCQASESLYNNNALAWFQQKPGQPPKRLIYDASKL ASGVPSRFSGGGSGTQFTLTISGVQCDDAATYYCGGYRSDSVDGVAFAGGTEVVV KR (SEQ ID NO: 121).
  • the invention also includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a light chain sequence comprising the sequence set forth below: AIVMTQTPSSKSVPVGDTVTINCQASESLYNNNALAWFQQKPGQPPKRLIYDASKL ASGVPSRFSGGGSGTQFTLTISGVQCDDAATYYCGGYRSDSVDGVAFAGGTEVVV KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
  • the invention further includes chimeric antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable heavy chain sequence comprising the sequence set forth below: QSVEESGGGLVQPEGSLTLTCTASGFDFSSNAMWWVRQAPGKGLEWIGIIYNGDG STYYASWVNGRFSISKTSSTTVTLQLNSLTVADTATYYCARDLDLWGPGTLVTVS
  • the invention also includes chimeric antibodies for the treatment or prevention of CGPvP-associated diarrhea having binding specificity to CGRP and possessing a heavy chain sequence comprising the sequence set forth below:
  • the invention further contemplates antibodies for the treatment or prevention of CGRP-associated diarrhea comprising one or more of the polypeptide sequences of SEQ ID NO: 125; SEQ ID NO: 126; and SEQ ID NO: 127 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 121 or the light chain sequence of SEQ ID NO: 122, and/or one or more of the polypeptide sequences of SEQ ID NO: 128; SEQ ID NO: 129; and SEQ ID NO: 130 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 123 or the heavy chain sequence of SEQ ID NO: 124, or combinations of these polypeptide sequences.
  • CDRs complementarity-determining regions
  • the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.
  • the invention also contemplates fragments of the antibody for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP.
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 121 or SEQ ID NO: 122.
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 123 or SEQ ID NO: 124.
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 125; SEQ ID NO: 126; and SEQ ID NO: 127 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 121 or the light chain sequence of SEQ ID NO: 122.
  • CDRs complementarity-determining regions
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 128; SEQ ID NO: 129; and SEQ ID NO: 130 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 123 or the heavy chain sequence of SEQ ID NO: 124.
  • CDRs complementarity-determining regions
  • fragments of the antibodies having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 121; the variable heavy chain region of SEQ ID NO: 123; the complementarity-determining regions (SEQ ID NO: 125; SEQ ID NO: 126; and SEQ ID NO: 127) of the variable light chain region of SEQ ID NO: 121; and the complementarity- determining regions (SEQ ID NO: 128; SEQ ID NO: 129; and SEQ ID NO: 130) of the variable heavy chain region of SEQ ID NO: 123.
  • the chimeric anti-CGRP antibody for the treatment or prevention of CGRP-associated diarrhea is Abl3, comprising, or alternatively consisting of, SEQ ID NO: 122 and SEQ ID NO: 124, and having at least one of the biological activities set forth herein.
  • antibody fragments comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • Fab fragment antigen binding
  • the Fab fragment for the treatment or prevention of CGRP-associated diarrhea includes the variable light chain sequence of SEQ ID NO: 121 and the variable heavy chain sequence of SEQ ID NO: 123.
  • This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 121 and/or SEQ ID NO: 123 in said Fab while retaining binding specificity for CGRP.
  • Fab fragments for the treatment or prevention of CGRP-associated diarrhea may be produced by enzymatic digestion (e.g., papain) of Abl3.
  • anti-CGRP antibodies for the treatment or prevention of CGRP-associated diarrhea such as Abl3 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable light chain sequence comprising the sequence set forth below: QVLTQSPSSLSASVGDRVTINCQASQNVYNNNYLAWYQQKPGKVPKQLIYSTSTL ASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGSYDCSRGDCFVFGGGTKVEIK
  • the invention also includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a light chain sequence comprising the sequence set forth below: QVLTQSPSSLSASVGDRVTINCQASQNVYNNNYLAWYQQKPGKVPKQLIYSTSTL ASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGSYDCSRGDCFVFGGGTKVEIK RT V AAP S VFIFPPSDEQLKS GT AS V VCLLNNF YPRE AKVQ WKVDN ALQ S GNS QE S VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
  • the invention further includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a variable heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAVSGIGLSSYYMQWVRQAPGKGLEWVGVIGSD GKTYYATWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCTRGDIWGQGTLVT VSS (SEQ ID NO: 133).
  • the invention also includes humanized antibodies for the treatment or prevention of CGRP-associated diarrhea having binding specificity to CGRP and possessing a heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAVSGIGLSSYYMQWVRQAPGKGLEWVGVIGSD GKTYYATWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCTRGDIWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF P AVLQ S S GL YSL S SWT VP S S SLGTQT YI CN VNHKP SNTKVD ARVEPKS CDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE
  • the invention further contemplates antibodies for the treatment or prevention of CGRP-associated diarrhea comprising one or more of the polypeptide sequences of SEQ ID NO: 135; SEQ ID NO: 136; and SEQ ID NO: 137 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 131 or the light chain sequence of SEQ ID NO: 132, and/or one or more of the polypeptide sequences of SEQ ID NO: 138; SEQ ID NO: 139; and SEQ ID NO: 140 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 133 or the heavy chain sequence of SEQ ID NO: 134, or combinations of these polypeptide sequences.
  • the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and
  • the invention also contemplates fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea.
  • antibody fragments of the invention for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 131 or SEQ ID NO: 132.
  • antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 133 or SEQ ID NO: 134.
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 135; SEQ ID NO: 136; and SEQ ID NO: 137 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 131 or the light chain sequence of SEQ ID NO: 132.
  • CDRs complementarity-determining regions
  • fragments of the antibody having binding specificity to CGRP for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 138; SEQ ID NO: 139; and SEQ ID NO: 140 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 133 or the heavy chain sequence of SEQ ID NO: 134.
  • CDRs complementarity-determining regions
  • the invention also contemplates antibody fragments for the treatment or prevention of CGRP-associated diarrhea which include one or more of the antibody fragments described herein.
  • fragments of the antibodies having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 131; the variable heavy chain region of SEQ ID NO: 133; the complementarity-determining regions (SEQ ID NO: 135; SEQ ID NO: 136; and SEQ ID NO: 137) of the variable light chain region of SEQ ID NO: 131; and the complementarity- determining regions (SEQ ID NO: 138; SEQ ID NO: 139; and SEQ ID NO: 140) of the variable heavy chain region of SEQ ID NO: 133.
  • the humanized anti- CGRP antibody for the treatment or prevention of CGRP-associated diarrhea is Abl4, comprising, or alternatively consisting of, SEQ ID NO: 132 and SEQ ID NO: 134, and having at least one of the biological activities set forth herein.
  • antibody fragments for the treatment or prevention of CGRP-associated diarrhea comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • the Fab fragment includes the variable light chain sequence of SEQ ID NO: 131 and the variable heavy chain sequence of SEQ ID NO: 133.
  • This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 131 and/or SEQ ID NO: 133 in said Fab while retaining binding specificity for CGRP.
  • Fab fragments for the treatment or prevention of CGRP-associated diarrhea may be produced by enzymatic digestion (e.g., papain) of Abl4.
  • anti-CGRP antibodies such as Abl4 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • antibody fragments may be present in one or more of the following non-limiting forms: Fab, Fab', F(ab')2, Fv and single chain Fv antibody forms.
  • the anti-CGRP antibodies described herein for the treatment or prevention of CGRP-associated diarrhea further comprises the kappa constant light chain sequence comprising the sequence set forth below:
  • the anti-CGRP antibodies described herein for the treatment or prevention of CGRP-associated diarrhea further comprises the gamma- 1 constant heavy chain polypeptide sequence comprising the sequence set forth below:
  • the invention contemplates an isolated anti-CGRP antibody for the treatment or prevention of CGRP-associated diarrhea comprising a VH polypeptide sequence selected from: SEQ ID NO: 3, 13, 23, 33, 43, 53, 63, 73, 83, 93, 103, 113, 123, or 133, or a variant thereof; and further comprising a VL polypeptide sequence selected from: SEQ ID NO: 1, 11, 21, 31, 41, 51, 61, 71, 81, 91, 101, 111, 121, or 131, or a variant thereof, wherein one or more of the framework residues (FR residues) in said VH or VL polypeptide has been substituted with another amino acid residue resulting in an anti- CGRP antibody that specifically binds CGRP.
  • VH polypeptide sequence selected from: SEQ ID NO: 3, 13, 23, 33, 43, 53, 63, 73, 83, 93, 103, 113, 123, or 133, or a variant thereof
  • the invention contemplates humanized and chimeric forms of these antibodies for the treatment or prevention of CGRP-associated diarrhea.
  • the chimeric antibodies may include an Fc derived from IgGl, IgG2, IgG3, IgG4, IgG5, IgG6, IgG7, IgG8, IgG9, IgGlO, IgGl l, IgG12, IgG13, IgG14, IgG15, IgG16, IgGl 7, IgGl 8 or IgGl 9 constant regions.
  • the antibodies or VH or VL polypeptides for the treatment or prevention of CGRP-associated diarrhea originate or are selected from one or more rabbit B cell populations prior to initiation of the humanization process referenced herein.
  • the anti-CGRP antibodies and fragments thereof for the treatment or prevention of CGRP-associated diarrhea do not have binding specificity for CGRP-R.
  • the anti-CGRP antibodies and fragments thereof inhibit the association of CGRP with CGRP-R.
  • the anti-CGRP antibodies and fragments thereof for the treatment or prevention of CGRP-associated diarrhea inhibit the association of CGRP with CGRP-R and/or additional proteins and/or multimers thereof, and/or antagonizes the biological effects thereof.
  • antibodies and fragments thereof for the treatment or prevention of CGRP-associated diarrhea may be modified post-translationally to add effector moieties such as chemical linkers, detectable moieties such as for example fluorescent dyes, enzymes, substrates, bioluminescent materials, radioactive materials, and chemiluminescent moieties, or functional moieties such as for example streptavidin, avidin, biotin, a cytotoxin, a cytotoxic agent, and radioactive materials.
  • effector moieties such as chemical linkers, detectable moieties such as for example fluorescent dyes, enzymes, substrates, bioluminescent materials, radioactive materials, and chemiluminescent moieties, or functional moieties such as for example streptavidin, avidin, biotin, a cytotoxin, a cytotoxic agent, and radioactive materials.
  • Antibodies or fragments thereof may also be chemically modified to provide additional advantages such as increased solubility, stability and circulating time (in vivo half-life) of the polypeptide, or decreased immunogenicity (See U.S. Pat. No. 4,179,337).
  • the chemical moieties for derivitization may be selected from water soluble polymers such as polyethylene glycol, ethylene glycol/propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol and the like.
  • the antibodies and fragments thereof may be modified at random positions within the molecule, or at predetermined positions within the molecule and may include one, two, three or more attached chemical moieties.
  • the polymer may be of any molecular weight, and may be branched or unbranched.
  • the preferred molecular weight is between about 1 kDa and about 100 kDa (the term "about” indicating that in preparations of polyethylene glycol, some molecules will weigh more, some less, than the stated molecular weight) for ease in handling and manufacturing.
  • Other sizes may be used, depending on the desired therapeutic profile (e.g., the duration of sustained release desired, the effects, if any on biological activity, the ease in handling, the degree or lack of antigenicity and other known effects of the polyethylene glycol to a therapeutic protein or analog).
  • the polyethylene glycol may have an average molecular weight of about 200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000, 10,500, 11,000, 11,500, 12,000, 12,500, 13,000, 13,500, 14,000, 14,500, 15,000, 15,500, 16,000, 16,500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, 20,000, 25,000, 30,000, 35,000, 40,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, 95,000, or 100,000 kDa.
  • Branched polyethylene glycols are described, for example, in U.S. Pat. No. 5,643,575; Morpurgo et al, Appl. Biochem. Biotechnol. 56:59-72 (1996); Vorobjev et al., Nucleosides Nucleotides 18:2745-2750 (1999); and Caliceti et al, Bioconjug. Chem. 10:638-646 (1999), the disclosures of each of which are incorporated herein by reference.
  • polyethylene glycol may be covalently bound through amino acid residues via a reactive group, such as, a free amino or carboxyl group.
  • Reactive groups are those to which an activated polyethylene glycol molecule may be bound.
  • the amino acid residues having a free amino group may include lysine residues and the N- terminal amino acid residues; those having a free carboxyl group may include aspartic acid residues glutamic acid residues and the C-terminal amino acid residue.
  • Sulfhydryl groups may also be used as a reactive group for attaching the polyethylene glycol molecules. Preferred for therapeutic purposes is attachment at an amino group, such as attachment at the N-terminus or lysine group.
  • polyethylene glycol may be attached to proteins via linkage to any of a number of amino acid residues.
  • polyethylene glycol can be linked to polypeptides via covalent bonds to lysine, histidine, aspartic acid, glutamic acid, or cysteine residues.
  • One or more reaction chemistries may be employed to attach polyethylene glycol to specific amino acid residues (e.g., lysine, histidine, aspartic acid, glutamic acid, or cysteine) or to more than one type of amino acid residue (e.g., lysine, histidine, aspartic acid, glutamic acid, cysteine and combinations thereof).
  • antibodies or fragments thereof for the treatment or prevention of CGRP-associated diarrhea may have increased in vivo half lives via fusion with albumin (including but not limited to recombinant human serum albumin or fragments or variants thereof (See, e.g., U.S. Pat. No. 5,876,969, issued Mar. 2, 1999, EP Patent 0 413 622, and U.S. Pat. No. 5,766,883, issued Jun. 16, 1998, herein incorporated by reference in their entirety)) or other circulating blood proteins such as transferrin or ferritin.
  • albumin including but not limited to recombinant human serum albumin or fragments or variants thereof (See, e.g., U.S. Pat. No. 5,876,969, issued Mar. 2, 1999, EP Patent 0 413 622, and U.S. Pat. No. 5,766,883, issued Jun. 16, 1998, herein incorporated by reference in their entirety)
  • other circulating blood proteins such as transferrin or ferritin.
  • polypeptides and/or antibodies of the present invention are fused with the mature form of human serum albumin (i.e., amino acids 1-585 of human serum albumin as shown in FIGS. 1 and 2 of EP Patent 0 322 094) which is herein incorporated by reference in its entirety.
  • Polynucleotides encoding fusion proteins of the invention are also encompassed by the invention.
  • further exemplary enzymes include, but are not limited to, horseradish peroxidase, acetylcholinesterase, alkaline phosphatase, beta- galactosidase and luciferase.
  • Further exemplary fluorescent materials include, but are not limited to, rhodamine, fluorescein, fluorescein isothiocyanate, umbelliferone, dichlorotriazinylamine, phycoerythrin and dansyl chloride.
  • Further chemiluminescent moieties include, but are not limited to, luminol.
  • Further exemplary bioluminescent materials include, but are not limited to, luciferin and aequorin.
  • Further exemplary radioactive materials include, but are not limited to, Iodine 125 (1251), Carbon 14 (14C), Sulfur 35 (35S), Tritium (3H) and Phosphorus 32 (32P).
  • exemplary cytotoxic agents include, but are not limited to, methotrexate, aminopterin, 6-mercaptopurine, 6-thioguanine, cytarabine, 5- fluorouracil decarbazine; alkylating agents such as mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU), mitomycin C, lomustine (CCNU), 1-methylnitrosourea, cyclothosphamide, mechlorethamine, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamine platinum (II) (DDP) cisplatin and carboplatin (paraplatin); anthracyclines include daunorubicin (formerly daunomycin), doxorubicin (adriamycin), detorubicin, carminomycin, idarubicin, epirub
  • cytotoxic agents include paclitaxel (taxol), ricin, pseudomonas exotoxin, gemcitabine, cytochalasin B, gramicidin D, ethidium bromide, emetine, etoposide, tenoposide, colchicin, dihydroxy anthracin dione, 1- dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, procarbazine, hydroxyurea, asparaginase, corticosteroids, mytotane ( ⁇ , ⁇ '- (DDD)), interferons, and mixtures of these cytotoxic agents.
  • taxol taxol
  • ricin pseudomonas exotoxin
  • gemcitabine cytochalasin B
  • gramicidin D ethidium bromide
  • emetine emetine
  • etoposide tenoposide
  • cytotoxic agents include, but are not limited to, chemotherapeutic agents such as carboplatin, cisplatin, paclitaxel, gemcitabine, calicheamicin, doxorubicin, 5- fluorouracil, mitomycin C, actinomycin D, cyclophosphamide, vincristine and bleomycin.
  • chemotherapeutic agents such as carboplatin, cisplatin, paclitaxel, gemcitabine, calicheamicin, doxorubicin, 5- fluorouracil, mitomycin C, actinomycin D, cyclophosphamide, vincristine and bleomycin.
  • Toxic enzymes from plants and bacteria such as ricin, diphtheria toxin and Pseudomonas toxin may be conjugated to the humanized or chimeric antibodies, or binding fragments thereof, to generate cell-type-specific-killing reagents (Youle, et al, Proc.
  • cytotoxic agents include cytotoxic ribonucleases as described by Goldenberg in U.S. Pat. No. 6,653,104.
  • Embodiments of the invention also relate to radioimmunoconjugates where a radionuclide that emits alpha or beta particles is stably coupled to the antibody, or binding fragments thereof, with or without the use of a complex-forming agent.
  • Such radionuclides include beta-emitters such as Phosphorus-32 (32P), Scandium-47 (47Sc), Copper-67 (67Cu), Gallium-67 (67Ga), Yttrium-88 (88Y), Yttrium-90 (90Y), Iodine-125 (1251), Iodine-131 (1311), Samarium-153 (153Sm), Lutetium-177 (177Lu), Rhenium-186 (186Re) or Rhenium-188 (188Re), and alpha- emitters such as Astatine-211 (211At), Lead-212 (212Pb), Bismuth-212 (212Bi) or -213 (213Bi) or Actinium-225 (225 Ac).
  • beta-emitters such as Phosphorus-32 (32P), Scandium-47 (47Sc), Copper-67 (67Cu), Gallium-67 (67Ga), Yttrium-88 (88Y), Yttrium-90 (90Y), Io
  • Embodiments described herein further include variants and equivalents that are substantially homologous to the antibodies, antibody fragments, diabodies, SMIPs, camelbodies, nanobodies, IgNAR, polypeptides, variable regions and CDRs set forth herein.
  • These may contain, e.g., conservative substitution mutations, (i.e., the substitution of one or more amino acids by similar amino acids).
  • conservative substitution refers to the substitution of an amino acid with another within the same general class, e.g., one acidic amino acid with another acidic amino acid, one basic amino acid with another basic amino acid, or one neutral amino acid by another neutral amino acid. What is intended by a conservative amino acid substitution is well known in the art.
  • the invention contemplates polypeptide sequences having at least 90% or greater sequence homology to any one or more of the polypeptide sequences of antibody fragments, variable regions and CDRs set forth herein. More preferably, the invention contemplates polypeptide sequences having at least 95% or greater sequence homology, even more preferably at least 98%> or greater sequence homology, and still more preferably at least 99% or greater sequence homology to any one or more of the polypeptide sequences of antibody fragments, variable regions and CDRs set forth herein. Methods for determining homology between nucleic acid and amino acid sequences are well known to those of ordinary skill in the art.
  • the invention further contemplates the above-recited polypeptide homologs of the antibody fragments, variable regions and CDRs set forth herein further having anti-CGRP activity.
  • anti-CGRP activity are set forth herein, for example, in paragraphs [0329]-[0350] infra.
  • the invention further contemplates the generation and use of anti-idiotypic antibodies that bind any of the foregoing sequences.
  • an anti-idiotypic antibody could be administered to a subject who has received an anti-CGRP antibody to modulate, reduce, or neutralize, the effect of the anti- CGRP antibody.
  • Such anti-idiotypic antibodies could also be useful for treatment of an autoimmune disease characterized by the presence of anti-CGRP antibodies.
  • a further exemplary use of such anti-idiotypic antibodies is for detection of the anti-CGRP antibodies of the present invention, for example to monitor the levels of the anti-CGRP antibodies present in a subject's blood or other bodily fluids.
  • the present invention also contemplates anti-CGRP antibodies comprising any of the polypeptide or polynucleotide sequences described herein substituted for any of the other polynucleotide sequences described herein.
  • the present invention contemplates antibodies comprising the combination of any of the variable light chain and variable heavy chain sequences described herein, and further contemplates antibodies resulting from substitution of any of the CDR sequences described herein for any of the other CDR sequences described herein.
  • the invention contemplates one or more anti-human CGRP antibodies or antibody fragments thereof for the treatment or prevention of CGRP- associated diarrhea which specifically bind to the same linear or conformational epitope(s) and/or competes for binding to the same linear or conformational epitope(s) on an intact human CGRP polypeptide or fragment thereof as an anti-human CGRP antibody selected from Abl, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, AblO, AM I, Abl2, Abl3, or Abl4.
  • the anti-human CGRP antibody or fragment thereof specifically binds to the same linear or conformational epitope(s) and/or competes for binding to the same linear or conformational epitope(s) on an intact human CGRP polypeptide or a fragment thereof as Ab3, Ab6, Abl3, Abl2 or Abl4.
  • a preferred embodiment of the invention is directed to chimeric or humanized antibodies and fragments thereof (including Fab fragments) having binding specificity for CGRP and inhibiting biological activities mediated by the binding of CGRP to the CGRP receptor for the treatment or prevention of CGRP-associated diarrhea.
  • the chimeric or humanized anti-CGRP antibodies for the treatment or prevention of CGRP-associated diarrhea are selected from Ab3, Ab6, AblO, Abl3, or Abl4.
  • a preferred embodiment of the invention is directed to methods of screening antibodies and fragments thereof (including Fab fragments) having binding specificity to human Calcitonin Gene Related Peptide (hereinafter "CGRP") in animal models to determine the in vivo effects thereof, especially their ability to antagonize the adverse side effects of CGRP including CGRP-associated diarrhea and to treat conditions involving excess CGRP.
  • CGRP Calcitonin Gene Related Peptide
  • Another more specific preferred embodiment of the invention involves a method of assessing the potential in vivo efficacy of a candidate anti-CGRP antibody or antibody fragment comprising determining whether the antibody inhibits CGRP associated diarrhea compared to a rodent administered CGRP in the absence of the candidate CGRP antibody or antibody fragment.
  • a more specific preferred embodiment of the invention involves a method of assessing the potential in vivo efficacy of a candidate anti-CGRP antibody or antibody fragment to treat a neurological condition characterized by increased CGRP levels.
  • Another more specific preferred embodiment of the invention involves a method of assessing the potential in vivo efficacy of a candidate anti-CGRP antibody or antibody fragment to treat a CGRP associated disorder associated with diarrhea such as migraine or chronic migraine, (with or without aura), weight loss, cancer or tumors, angiogenesis associated with cancer or tumor growth, angiogenesis associated with cancer or tumor survival, hemiplagic migraines, cluster headaches, migrainous neuralgia, chronic headaches, tension headaches, general headaches, hot flushes, chronic paroxysomal hemicrania, secondary headaches due to an underlying structural problem in the head or neck, cranial neuralgia, sinus headaches (such as for example associated with sinusitis), allergy-induced headaches or migraines, pain, inflammatory pain, post-operative incision pain, complex regional pain syndrome, cancer pain, primary or metastatic bone cancer pain, fracture pain, chronic pain, osteoporotic fracture pain, pain resulting from burn, osteoporosis, gout joint pain, abdominal pain, pain
  • Another more specific preferred embodiment of the invention involves a method of using an anti-CGRP antibody or antibody fragment to treat a CGRP associated disorder associated with diarrhea wherein the condition is cancer pain arising from malignancy or from cancer preferably selected from one or more of: adenocarcinoma in glandular tissue, blastoma in embryonic tissue of organs, carcinoma in epithelial tissue, leukemia in tissues that form blood cells, lymphoma in lymphatic tissue, myeloma in bone marrow, sarcoma in connective or supportive tissue, adrenal cancer, AIDS-related lymphoma, anemia, bladder cancer, bone cancer, brain cancer, breast cancer, carcinoid tumours, cervical cancer, chemotherapy, colon cancer, cytopenia, endometrial cancer, esophageal cancer, gastric cancer, head cancer, neck cancer, hepatobiliary cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, Hodgkin's disease, lymphoma, non- Hod
  • the cancer pain comprises visceral pain, preferably visceral pain which arises from pancreatic cancer and/or metastases in the abdomen.
  • the cancer pain comprises somatic pain, preferably somatic pain due to one or more of bone cancer, metastasis in the bone, postsurgical pain, sarcomas cancer of the connective tissue, cancer of bone tissue, cancer of blood-forming cells of the bone marrow, multiple myeloma, leukaemia, primary or secondary bone cancer.
  • a further another preferred embodiment of the invention relates to methods of inhibiting, preventing or treating diarrhea and/or maintaining electrolyte balance and fluid levels in the intestines of a subject having a condition associated with elevated CGRP levels that result in diarrhea and/or increased flux of electrolytes and fluids from the intestines comprising administering an effective amount of an anti-CGRP antibody or anti- CGRP antibody fragment.
  • Another preferred embodiment of the invention specifically relates to methods of treating or preventing diarrhea in individuals with functional bowel disorders or an inflammatory bowel diseases, bacterial or viral induced diarrhea, cancer associated with diarrhea, such as medullary thyroid carcinoma or a colorectal cancer, and more specifically functional bowel disorders or inflammatory bowel diseases, including by way of example gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, functional abdominal pain syndrome, diverticulosis, and diverticulitis or inflammatory bowel disease is selected from the group consisting of Crohn's disease, ileitis, collagenous colitis, lymphocytic colitis, and ulcerative colitis wherein these therapies administer an effective amount of an anti-CGRP antibody or antibody fragment administered as a monotherapy or in combination with another active agent.
  • these therapies administer an effective amount of an anti-CGRP antibody or antibody fragment administered as a monotherapy or in combination with another active agent.
  • the present invention are directed to screening assays and therapeutic usage of specific antibodies and fragments thereof having binding specificity for CGRP, in particular antibodies having desired epitopic specificity, high affinity or avidity and/or functional properties.
  • this invention relates to assays and usage of the antibodies described herein, comprising the sequences of the VH, VL and CDR polypeptides described herein, and the polynucleotides encoding them.
  • a preferred embodiment of the invention is directed to chimeric or humanized antibodies and fragments thereof (including Fab fragments) capable of binding to CGRP and/or inhibiting the biological activities mediated by the binding of CGRP to the CGRP receptor ("CGRP-R").
  • a further embodiment of the invention is contemplated a method of reducing, treating or preventing diseases or disorders associated with CGRP which may include diarrhea as an adverse side effect by affecting those biological activities mediated via CGRP, thereby avoiding the biological activities mediated via binding of CGRP to CGRP- R.
  • diseases and disorders associated with CGRP may include diarrhea as an adverse side effect by affecting those biological activities mediated via CGRP, thereby avoiding the biological activities mediated via binding of CGRP to CGRP- R.
  • the anti-human CGRP antibody for the treatment or prevention of CGRP-associated diarrhea is an antibody which specifically binds to the same linear or conformational epitopes on an intact CGRP polypeptide or fragment thereof that is (are) specifically bound by Ab3, Ab6, Abl3, or Abl4 as ascertained by epitopic mapping using overlapping linear peptide fragments which span the full length of the native human CGRP polypeptide.
  • the invention is also directed to an anti-CGRP antibody for the treatment or prevention of CGRP-associated diarrhea that binds with the same CGRP epitope and/or competes with an anti-CGRP antibody for binding to CGRP as an antibody or antibody fragment disclosed herein, including but not limited to an anti-CGRP antibody selected from Abl, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, AblO, Abl 1, Abl2, Abl3, or Abl4.
  • the invention is also directed to an isolated anti-CGRP antibody or antibody fragment for the treatment or prevention of CGRP-associated diarrhea comprising one or more of the CDRs contained in the VH polypeptide sequences selected from: 3, 13, 23, 33, 43, 53, 63, 73, 83, 93, 103, 113, 123, or 133, or a variant thereof, and/or one or more of the CDRs contained in the VL polypeptide sequences selected from: 1, 11, 21, 31, 41, 51, 61, 71, 81, 91, 101, 111, 121, or 131, or a variant thereof.
  • the anti-human CGRP antibody discussed in the two prior paragraphs comprises at least 2 complementarity determining regions (CDRs) in each the variable light and the variable heavy regions which are identical to those contained in an anti-human CGRP antibody selected from Abl, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, AblO, AM I, Abl2, Abl3, or Abl4.
  • CDRs complementarity determining regions
  • the anti-human CGRP antibody discussed above comprises at least 2 complementarity determining regions (CDRs) in each the variable light and the variable heavy regions which are identical to those contained in Ab3 or Ab6.
  • CDRs complementarity determining regions
  • all of the CDRs of the anti-human CGRP antibody discussed above are identical to the CDRs contained in an anti-human CGRP antibody selected from Abl, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, AblO, AM I, Abl2, Abl3, or Abl4.
  • all of the CDRs of the anti-human CGRP antibody discussed above are identical to the CDRs contained in an anti-human CGRP antibody selected from Ab3 or Ab6.
  • the invention further contemplates that the one or more anti-human CGRP antibodies discussed above for the treatment or prevention of CGRP-associated diarrhea which are aglycosylated; or minimally glycosylated, e.g., which lack N-glycosylation but may comprise some O-glycosylation, such as mannose residues, and/or that contain an Fc region that has been modified to alter effector function, half-life, proteolysis, and/or glycosylation; are human, humanized, single chain or chimeric; and are a humanized antibody derived from a rabbit (parent) anti-human CGRP antibody.
  • the invention further contemplates one or more anti-human CGRP antibodies for the treatment or prevention of CGRP-associated diarrhea
  • the framework regions (FRs) in the variable light region and the variable heavy regions of said antibody respectively are human FRs which are unmodified or which have been modified by the substitution of one or more human FR residues in the variable light or heavy chain region with the corresponding FR residues of the parent rabbit antibody
  • said human FRs have been derived from human variable heavy and light chain antibody sequences which have been selected from a library of human germline antibody sequences based on their high level of homology to the corresponding rabbit variable heavy or light chain regions relative to other human germline antibody sequences contained in the library.
  • the anti-human CGRP antibody or fragment for the treatment or prevention of CGRP-associated diarrhea specifically binds to CGRP expressing human cells and/or to circulating soluble CGRP molecules in vivo, including CGRP expressed on or by human cells in a patient with a disease associated with cells that express CGRP.
  • the CGRP related disease that may be associated with diarrhea is selected from migraines (with or without aura), weight loss, cancer or tumors, angiogenesis associated with cancer or tumor growth, angiogenesis associated with cancer or tumor survival, hemiplagic migraines, cluster headaches, migrainous neuralgia, chronic headaches, tension headaches, general headaches, hot flushes, chronic paroxysomal hemicrania, secondary headaches due to an underlying structural problem in the head or neck, cranial neuralgia, sinus headaches (such as for example associated with sinusitis), allergy-induced headaches or migraines, pain, inflammatory pain, post-operative incision pain, complex regional pain syndrome, cancer pain, primary or metastatic bone cancer pain, fracture pain, chronic pain, osteoporotic fracture pain, pain resulting from burn, osteoporosis, gout joint pain, abdominal pain, pain associated with sickle cell crises, and other nociceptic pain, as well as hepatocellular carcinoma, breast cancer, liver cirrhosis
  • the disease treated that may be associated with diarrhea is cancer pain arising from malignancy or from cancer preferably selected from one or more of: adenocarcinoma in glandular tissue, blastoma in embryonic tissue of organs, carcinoma in epithelial tissue, leukemia in tissues that form blood cells, lymphoma in lymphatic tissue, myeloma in bone marrow, sarcoma in connective or supportive tissue, adrenal cancer, AIDS-related lymphoma, anemia, bladder cancer, bone cancer, brain cancer, breast cancer, carcinoid tumours, cervical cancer, chemotherapy, colon cancer, cytopenia, , endometrial cancer, esophageal cancer, gastric cancer, head cancer, neck cancer, hepatobiliary cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, Hodgkin's disease, lymphoma, non- Hodgkin's, nervous system tumours, oral cancer, ovarian cancer, pancre
  • the cancer pain comprises visceral pain, preferably visceral pain which arises from pancreatic cancer and/or metastases in the abdomen.
  • the cancer pain comprises somatic pain, preferably somatic pain due to one or more of bone cancer, metastasis in the bone, postsurgical pain, sarcomas cancer of the connective tissue, cancer of bone tissue, cancer of blood-forming cells of the bone marrow, multiple myeloma, leukaemia, primary or secondary bone cancer.
  • the invention further contemplates anti-human CGRPantibodies or fragments diarrhea directly or indirectly attached to a detectable label or therapeutic agent.
  • the invention also contemplates one or more nucleic acid sequences which result in the expression of an anti-human CGRP antibody or antibody fragment as set forth above, including those comprising, or alternatively consisting of, yeast or human preferred codons.
  • the invention also contemplates vectors (including plasmids or recombinant viral vectors) comprising said nucleic acid sequence(s).
  • the invention also contemplates host cells or recombinant host cells expressing at least one of the antibodies set forth above, including a mammalian, yeast, bacterial, and insect cells.
  • the host cell is a yeast cell.
  • the yeast cell is a diploidal yeast cell.
  • the yeast cell is a Pichia yeast.
  • the invention also contemplates a method of treatment comprising administering to a patient with a disease or condition associated with CGRP expressing cells that results in diarrhea a therapeutically effective amount of at least one anti-human CGRP antibody or fragment described herein.
  • the invention also contemplates that the treatment method may involve the administration of two or more anti-CGRP antibodies or fragments thereof and disclosed herein. If more than one antibody is administered to the patient, the multiple antibodies may be administered simultaneously or concurrently, or may be staggered in their administration.
  • the diseases that may be treated are presented in the non-limiting list set forth above and elsewhere herein.
  • the disease is selected from migraine, headache, weight loss, pain, cancer pain or neuropathic pain.
  • the treatment further includes the administration of another therapeutic agent or regimen selected from chemotherapy, radiotherapy, cytokine administration or gene therapy.
  • another therapeutic agent or regimen includes opioids, analgesics such as NSAIDs, Taxol (paclitaxel) or its derivatives, platinum compounds such as carboplatin or cisplatin, anthrocyclines such as doxorubicin, alkylating agents such as cyclophosphamide, anti-metabolites such as 5-fluorouracil, or etoposide.
  • opioids such as NSAIDs, Taxol (paclitaxel) or its derivatives
  • platinum compounds such as carboplatin or cisplatin
  • anthrocyclines such as doxorubicin
  • alkylating agents such as cyclophosphamide
  • anti-metabolites such as 5-fluorouracil, or etoposide.
  • the invention further contemplates a method of in vivo imaging which detects the presence of cells which express CGRP comprising administering a diagnostically effective amount of at least one anti-human CGRP antibody.
  • said administration further includes the administration of a radionuclide or fluorophore that facilitates detection of the antibody at CGRP expressing disease sites.
  • the results of said in vivo imaging method are used to facilitate the design of an appropriate therapeutic regimen, including therapeutic regimens including radiotherapy, chemotherapy or a combination thereof.
  • the anti-CGRP activity of the anti-CGRP antibodies of the present invention, and fragments thereof having binding specificity to CGRP diarrhea may also be described by their strength of binding or their affinity for CGRP.
  • the anti-CGRP antibodies of the present invention, and fragments thereof having binding specificity to CGRP bind to CGRP with a dissociation constant (KD) of less than or equal to 5x10-7 M, 10-7 M, 5x10-8 M, 10-8 M, 5x10-9 M, 10-9 M, 5x10-10 M, 10-10 M, 5x10-11 M, 10-11 M, 5x10-12 M, 10-12 M, 5x10-13 M, or 10-13 M.
  • KD dissociation constant
  • the anti-CGRP antibodies and fragments thereof bind CGRP with a dissociation constant of less than or equal to 10-11 M, 5x10-12 M, or 10-12 M.
  • the anti-CGRP antibodies of the present invention, and fragments thereof having binding specificity to CGRP bind to a linear or conformational CGRP epitope.
  • the anti-CGRP activity of the anti- CGRP antibodies of the present invention, and fragments thereof having binding specificity to CGRP bind to CGRP with an off-rate of less than or equal to 10-4 S-l, 5x10-5 S-l, 10-5 S-l, 5x10-6 S-l, 10-6 S-l, 5x10-7 S-l, or 10-7 S-l .
  • the anti-CGRP activity of the anti- CGRP antibodies of the present invention, and fragments thereof having binding specificity to CGRP exhibit anti-CGRP activity by preventing, ameliorating or reducing the symptoms of, or alternatively treating, diseases and disorders associated with CGRP especially diarrhea.
  • diseases and disorders associated with CGRP are set forth herein.
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 1 :
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 2:
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 3:
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 4:
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 145; SEQ ID NO: 146; and SEQ ID NO: 147 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 1 or the light chain sequence of SEQ ID NO: 2.
  • CDRs complementarity-determining regions
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 148; SEQ ID NO: 149; and SEQ ID NO: 150 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 3 or the heavy chain sequence of SEQ ID NO: 4.
  • CDRs complementarity-determining regions
  • polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein.
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 141 encoding the light chain variable sequence of SEQ ID NO: 1; the polynucleotide SEQ ID NO: 142 encoding the light chain sequence of SEQ ID NO: 2; the polynucleotide SEQ ID NO: 143 encoding the heavy chain variable sequence of SEQ ID NO: 3; the polynucleotide SEQ ID NO: 144 encoding the heavy chain sequence of SEQ ID NO: 4; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 145
  • polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • the polynucleotides encoding the full length Abl antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 142 encoding the light chain sequence of SEQ ID NO: 2 and the polynucleotide SEQ ID NO: 144 encoding the heavy chain sequence of SEQ ID NO: 4.
  • Another embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, or microbial systems such as yeast cells such as the yeast Pichia.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Abl following expression of the full-length polynucleotides in a suitable host.
  • anti-CGRP antibodies such as Abl or Fab fragments thereof may be produced via expression of Abl polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • mammalian cells such as CHO, NSO or HEK 293 cells
  • fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • yeast cells for example diploid yeast such as diploid Pichia
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 11 :
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 12:
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 13:
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 14:
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 155; SEQ ID NO: 156; and SEQ ID NO: 157 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 11 or the light chain sequence of SEQ ID NO: 12.
  • CDRs complementarity-determining regions
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 158; SEQ ID NO: 159; and SEQ ID NO: 160 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 13 or the heavy chain sequence of SEQ ID NO: 14.
  • CDRs complementarity-determining regions
  • polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein.
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 151 encoding the light chain variable sequence of SEQ ID NO: 11; the polynucleotide SEQ ID NO: 152 encoding the light chain sequence of SEQ ID NO: 12; the polynucleotide SEQ ID NO: 153 encoding the heavy chain variable sequence of SEQ ID NO: 13; the polynucleotide SEQ ID NO: 154 encoding the heavy chain sequence of SEQ ID NO: 14; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 155
  • polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • the polynucleotides encoding the full length Ab2 antibody comprise, or alternatively consist of,the polynucleotide SEQ ID NO: 152 encoding the light chain sequence of SEQ ID NO: 12 and the polynucleotide SEQ ID NO: 154 encoding the heavy chain sequence of SEQ ID NO: 14.
  • Another embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, or microbial systems such as yeast cells such as the yeast Pichia.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab2 following expression of the full-length polynucleotides in a suitable host.
  • anti-CGRP antibodies such as Ab2 or Fab fragments thereof may be produced via expression of Ab2 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • mammalian cells such as CHO, NSO or HEK 293 cells
  • fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • yeast cells for example diploid yeast such as diploid Pichia
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 21 :
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 22:
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 23:
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 24:
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 165; SEQ ID NO: 166; and SEQ ID NO: 167 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 21 or the light chain sequence of SEQ ID NO: 22.
  • CDRs complementarity-determining regions
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 168; SEQ ID NO: 169; and SEQ ID NO: 170 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 23 or the heavy chain sequence of SEQ ID NO: 24.
  • CDRs complementarity-determining regions
  • polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein.
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 161 encoding the light chain variable sequence of SEQ ID NO: 21; the polynucleotide SEQ ID NO: 162 encoding the light chain sequence of SEQ ID NO: 22; the polynucleotide SEQ ID NO: 163 encoding the heavy chain variable sequence of SEQ ID NO: 23; the polynucleotide SEQ ID NO: 164 encoding the heavy chain sequence of SEQ ID NO: 24; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 165
  • polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • the polynucleotides encoding the full length Ab3 antibody comprise, or alternatively consist of,the polynucleotide SEQ ID NO: 162 encoding the light chain sequence of SEQ ID NO: 22 and the polynucleotide SEQ ID NO: 164 encoding the heavy chain sequence of SEQ ID NO: 24.
  • Another embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, or microbial systems such as yeast cells such as the yeast Pichia.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab3 following expression of the full-length polynucleotides in a suitable host.
  • anti-CGRP antibodies such as Ab3 or Fab fragments thereof may be produced via expression of Ab3 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • mammalian cells such as CHO, NSO or HEK 293 cells
  • fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • yeast cells for example diploid yeast such as diploid Pichia
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to CGRP.
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 31 :
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 32:
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 33:
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 34:
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 175; SEQ ID NO: 176; and SEQ ID NO: 177 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 31 or the light chain sequence of SEQ ID NO: 32.
  • CDRs complementarity-determining regions
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 178; SEQ ID NO: 179; and SEQ ID NO: 180 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 33 or the heavy chain sequence of SEQ ID NO: 34.
  • CDRs complementarity-determining regions
  • polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein.
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 171 encoding the light chain variable sequence of SEQ ID NO: 31; the polynucleotide SEQ ID NO: 172 encoding the light chain sequence of SEQ ID NO: 32; the polynucleotide SEQ ID NO: 173 encoding the heavy chain variable sequence of SEQ ID NO: 33; the polynucleotide SEQ ID NO: 174 encoding the heavy chain sequence of SEQ ID NO: 34; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 175
  • polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • the polynucleotides encoding the full length Ab4 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 172 encoding the light chain sequence of SEQ ID NO: 32 and the polynucleotide SEQ ID NO: 174 encoding the heavy chain sequence of SEQ ID NO: 34.
  • Another embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, or microbial systems such as yeast cells such as the yeast Pichia.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab4 following expression of the full-length polynucleotides in a suitable host.
  • anti-CGRP antibodies such as Ab4 or Fab fragments thereof may be produced via expression of Ab4 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • mammalian cells such as CHO, NSO or HEK 293 cells
  • fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • yeast cells for example diploid yeast such as diploid Pichia
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 41 :
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 42:
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 43:
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 44:
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 185; SEQ ID NO: 186; and SEQ ID NO: 187 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 41 or the light chain sequence of SEQ ID NO: 42.
  • CDRs complementarity-determining regions
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 188; SEQ ID NO: 189; and SEQ ID NO: 190 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 43 or the heavy chain sequence of SEQ ID NO: 44.
  • CDRs complementarity-determining regions
  • polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein.
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 181 encoding the light chain variable sequence of SEQ ID NO: 41; the polynucleotide SEQ ID NO: 182 encoding the light chain sequence of SEQ ID NO: 42; the polynucleotide SEQ ID NO: 183 encoding the heavy chain variable sequence of SEQ ID NO: 43; the polynucleotide SEQ ID NO: 184 encoding the heavy chain sequence of SEQ ID NO: 44; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 185;
  • polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • the polynucleotides encoding the full length Ab5 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 182 encoding the light chain sequence of SEQ ID NO: 42 and the polynucleotide SEQ ID NO: 184 encoding the heavy chain sequence of SEQ ID NO: 44.
  • Another embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, or microbial systems such as yeast cells such as the yeast Pichia.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab5 following expression of the full-length polynucleotides in a suitable host.
  • anti-CGRP antibodies such as Ab5 or Fab fragments thereof may be produced via expression of Ab5 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • mammalian cells such as CHO, NSO or HEK 293 cells
  • fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • yeast cells for example diploid yeast such as diploid Pichia
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 51 :
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 52:
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 53:
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 54:
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 195; SEQ ID NO: 196; and SEQ ID NO: 197 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 51 or the light chain sequence of SEQ ID NO: 52.
  • CDRs complementarity-determining regions
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 198; SEQ ID NO: 199; and SEQ ID NO: 200 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 53 or the heavy chain sequence of SEQ ID NO: 54.
  • CDRs complementarity-determining regions
  • polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein.
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 191 encoding the light chain variable sequence of SEQ ID NO: 51; the polynucleotide SEQ ID NO: 192 encoding the light chain sequence of SEQ ID NO: 52; the polynucleotide SEQ ID NO: 193 encoding the heavy chain variable sequence of SEQ ID NO: 53; the polynucleotide SEQ ID NO: 194 encoding the heavy chain sequence of SEQ ID NO: 54; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 195
  • polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • the polynucleotides encoding the full length Ab6 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 192 encoding the light chain sequence of SEQ ID NO: 52 and the polynucleotide SEQ ID NO: 194 encoding the heavy chain sequence of SEQ ID NO: 54.
  • Another embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, or microbial systems such as yeast cells such as the yeast Pichia.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab6 following expression of the full-length polynucleotides in a suitable host.
  • anti-CGRP antibodies such as Ab6 or Fab fragments thereof may be produced via expression of Ab6 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • mammalian cells such as CHO, NSO or HEK 293 cells
  • fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • yeast cells for example diploid yeast such as diploid Pichia
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 61 :
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 62:
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 63:
  • CTGGTCACCGTCTCGAGC SEQ ID NO: 203.
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 64:
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 205; SEQ ID NO: 206; and SEQ ID NO: 207 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 61 or the light chain sequence of SEQ ID NO: 62.
  • CDRs complementarity-determining regions
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 208; SEQ ID NO: 209; and SEQ ID NO: 210 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 63 or the heavy chain sequence of SEQ ID NO: 64.
  • CDRs complementarity-determining regions
  • polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein.
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 201 encoding the light chain variable sequence of SEQ ID NO: 61; the polynucleotide SEQ ID NO: 202 encoding the light chain sequence of SEQ ID NO: 62; the polynucleotide SEQ ID NO: 203 encoding the heavy chain variable sequence of SEQ ID NO: 63; the polynucleotide SEQ ID NO: 204 encoding the heavy chain sequence of SEQ ID NO: 64; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 201 encoding the light chain variable sequence of SEQ ID
  • polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • the polynucleotides encoding the full length Ab7 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 202 encoding the light chain sequence of SEQ ID NO: 62 and the polynucleotide SEQ ID NO: 204 encoding the heavy chain sequence of SEQ ID NO: 64.
  • Another embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, or microbial systems such as yeast cells such as the yeast Pichia.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab7 following expression of the full-length polynucleotides in a suitable host.
  • anti-CGRP antibodies such as Ab7 or Fab fragments thereof may be produced via expression of Ab7 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • mammalian cells such as CHO, NSO or HEK 293 cells
  • fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • yeast cells for example diploid yeast such as diploid Pichia
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 71 :
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 72:
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 73:
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 74:
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 215; SEQ ID NO: 216; and SEQ ID NO: 217 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 71 or the light chain sequence of SEQ ID NO: 72.
  • CDRs complementarity-determining regions
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 218; SEQ ID NO: 219; and SEQ ID NO: 220 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 73 or the heavy chain sequence of SEQ ID NO: 74.
  • CDRs complementarity-determining regions
  • polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein.
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 211 encoding the light chain variable sequence of SEQ ID NO: 71; the polynucleotide SEQ ID NO: 212 encoding the light chain sequence of SEQ ID NO: 72; the polynucleotide SEQ ID NO: 213 encoding the heavy chain variable sequence of SEQ ID NO: 73; the polynucleotide SEQ ID NO: 214 encoding the heavy chain sequence of SEQ ID NO: 74; polynucleotides encoding the complementarity-determining regions (SEQ ID NO:
  • polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • the polynucleotides encoding the full length Ab8 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 212 encoding the light chain sequence of SEQ ID NO: 72 and the polynucleotide SEQ ID NO: 214 encoding the heavy chain sequence of SEQ ID NO: 74.
  • Another embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, or microbial systems such as yeast cells such as the yeast Pichia.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab8 following expression of the full-length polynucleotides in a suitable host.
  • anti-CGRP antibodies such as Ab8 or Fab fragments thereof may be produced via expression of Ab8 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • mammalian cells such as CHO, NSO or HEK 293 cells
  • fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • yeast cells for example diploid yeast such as diploid Pichia
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 81 : [000504] CAAGTGCTGACCCAGACTCCATCCCCCGTGTCTGCAGCTGTGGGAAG
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 82:
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 83:
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 84:
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 225; SEQ ID NO: 226; and SEQ ID NO: 227 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 81 or the light chain sequence of SEQ ID NO: 82.
  • CDRs complementarity-determining regions
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 228; SEQ ID NO: 229; and SEQ ID NO: 230 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 83 or the heavy chain sequence of SEQ ID NO: 84.
  • CDRs complementarity-determining regions
  • polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein.
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 221 encoding the light chain variable sequence of SEQ ID NO: 81; the polynucleotide SEQ ID NO: 222 encoding the light chain sequence of SEQ ID NO: 82; the polynucleotide SEQ ID NO: 223 encoding the heavy chain variable sequence of SEQ ID NO: 83; the polynucleotide SEQ ID NO: 224 encoding the heavy chain sequence of SEQ ID NO: 84; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: ).
  • polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • the polynucleotides encoding the full length Ab9 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 222 encoding the light chain sequence of SEQ ID NO: 82 and the polynucleotide SEQ ID NO: 224 encoding the heavy chain sequence of SEQ ID NO: 84.
  • Another embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, or microbial systems such as yeast cells such as the yeast Pichia.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab9 following expression of the full-length polynucleotides in a suitable host.
  • anti-CGRP antibodies such as Ab9 or Fab fragments thereof may be produced via expression of Ab9 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • mammalian cells such as CHO, NSO or HEK 293 cells
  • fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • yeast cells for example diploid yeast such as diploid Pichia
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 91 :
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 92:
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 93:
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 94: [000523] gaggtgcagctTgtggagtctgggggaggcttggtccagcctggggggggtccctgagactctcctgtgcaGTCt ctggaATCGGCCTCagtAGCTACTACATGCAAtgggtccgtcaggctccagggaaggggctggagtgggt cGGAGTCATTGGTAGTGATGGTAAGACATACTACGCGACCTGGGCGAAAGGCcg attcaccatctccagagacaattccaagACCACGGTGtatcttcaaatgaacagcctgagagctgaggacactgctgtgtatat
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 235; SEQ ID NO: 236; and SEQ ID NO: 237 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 91 or the light chain sequence of SEQ ID NO: 92.
  • CDRs complementarity-determining regions
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 238; SEQ ID NO: 239; and SEQ ID NO:240 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 93 or the heavy chain sequence of SEQ ID NO: 94.
  • CDRs complementarity-determining regions
  • polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein.
  • polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 231 encoding the light chain variable sequence of SEQ ID NO: 91; the polynucleotide SEQ ID NO: 232 encoding the light chain sequence of SEQ ID NO: 92; the polynucleotide SEQ ID NO: 233 encoding the heavy chain variable sequence of SEQ ID NO: 93; the polynucleotide SEQ ID NO: 234 encoding the heavy chain sequence of SEQ ID NO: 94; polynucleotides encoding the complementarity-determining regions (SEQ ID NO:
  • polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for CGRP.
  • the polynucleotides encoding the full length AblO antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 232 encoding the light chain sequence of SEQ ID NO: 92 and the polynucleotide SEQ ID NO: 234 encoding the heavy chain sequence of SEQ ID NO: 94.
  • Another embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, or microbial systems such as yeast cells such as the yeast Pichia.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of AblO following expression of the full-length polynucleotides in a suitable host.
  • anti-CGRP antibodies such as AblO or Fab fragments thereof may be produced via expression of AblO polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains.
  • mammalian cells such as CHO, NSO or HEK 293 cells
  • fungal, insect or microbial systems
  • yeast cells for example diploid yeast such as diploid Pichia
  • yeast strains for example diploid yeast such as diploid Pichia
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 101 :
PCT/US2012/038869 2011-05-20 2012-05-21 Utilisation d'anticorps ou de fragments d'anticorps anti-cgrp ou anti-cgrp-r dans le traitement ou la prévention de formes chroniques et aiguës de la diarrhée WO2012162253A2 (fr)

Priority Applications (16)

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CN201810154696.1A CN108359008B (zh) 2011-05-20 2012-05-21 抗cgrp或抗cgrp-r抗体或抗体片段用于治疗或预防慢性和急性形式的腹泻的用途
EA201301292A EA033109B1 (ru) 2011-05-20 2012-05-21 Способы ингибирования, профилактики или лечения диареи и/или поддержания соответствующих уровней электролитов и жидкости в толстой кишке субъекта, подвергающегося связанному с диареей состоянию, с помощью антитела против cgrp или фрагмента антитела против cgrp
BR112013029951-7A BR112013029951B1 (pt) 2011-05-20 2012-05-21 composição farmacêutica e uso de anticorpos ou fragmentos de anticorpos anti-cgrp para tratar ou prevenir formas de diarreia crônicas e agudas
NZ618639A NZ618639B2 (en) 2011-05-20 2012-05-21 Use of anti-cgrp or anti-cgrp-r antibodies or antibody fragments to treat or prevent chronic and acute forms of diarrhea
AU2012258976A AU2012258976B8 (en) 2011-05-20 2012-05-21 Use of anti-CGRP or anti-CGRP-R antibodies or antibody fragments to treat or prevent chronic and acute forms of diarrhea
EP12788717.2A EP2709662B1 (fr) 2011-05-20 2012-05-21 Utilisation d'anticorps ou de fragments d'anticorps anti-cgrp ou anti-cgrp-r dans le traitement ou la prévention de formes chroniques et aiguës de la diarrhée
DK12788717T DK2709662T3 (da) 2011-05-20 2012-05-21 Anvendelse af anti-cgrp- eller anti-cgrp-r-antistoffer eller antistoffragmenter til behandling eller forebyggelse af kroniske og akutte former for diarré
CA2836799A CA2836799C (fr) 2011-05-20 2012-05-21 Utilisation d'anticorps ou de fragments d'anticorps anti-cgrp ou anti-cgrp-r dans le traitement ou la prevention de formes chroniques et aigues de la diarrhee
KR1020137033852A KR102128628B1 (ko) 2011-05-20 2012-05-21 설사의 만성 및 급성 형태를 치료 또는 예방하기 위한 항-cgrp 또는 항-cgrp-r 항체 또는 항체 단편의 용도
CN201280035841.5A CN103957935B (zh) 2011-05-20 2012-05-21 抗cgrp或抗cgrp‑r抗体或抗体片段用于治疗或预防慢性和急性形式的腹泻的用途
JP2014512928A JP6189832B2 (ja) 2011-05-20 2012-05-21 慢性および急性の下痢を治療または予防するための抗ｃｇｒｐ若しくは抗ｃｇｒｐ−ｒの抗体または抗体断片の使用
MX2013013534A MX365813B (es) 2011-05-20 2012-05-21 Uso de anticuerpos anti-cgrp o anti-cgrp o fragmentos de anticuerpo para tratar o prevenir formas crónicas y agudas de diarrea.
SG2013084587A SG194974A1 (en) 2011-05-20 2012-05-21 Use of anti-cgrp or anti-cgrp-r antibodies or antibody fragments to treat or prevent chronic and acute forms of diarrhea
IL229433A IL229433B (en) 2011-05-20 2013-11-14 Use of antibodies against cgrp or r-cgrp or antibody fragments for the treatment or prevention of chronic or acute diarrhea
AU2017239524A AU2017239524B2 (en) 2011-05-20 2017-10-04 Use of anti-CGRP or anti-CGRP-R antibodies or antibody fragments to treat or prevent chronic and acute forms of diarrhea
AU2019202643A AU2019202643B2 (en) 2011-05-20 2019-04-16 Use of anti-CGRP or anti-CGRP-R antibodies or antibody fragments to treat or prevent chronic and acute forms of diarrhea

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US201161488660P 2011-05-20 2011-05-20
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016528198A (ja) * 2013-07-03 2016-09-15 アルダー・バイオファーマシューティカルズ・インコーポレーテッド 抗ｃｇｒｐ抗体を使用したグルコース代謝の調整
US9896502B2 (en) 2014-03-21 2018-02-20 Teva Pharmaceuticals International Gmbh Antagonist antibodies directed against calcitonin gene-related peptide and methods using same
US10392434B2 (en) 2016-09-23 2019-08-27 Teva Pharmaceuticals International Gmbh Treating refractory migraine
US10556945B2 (en) 2014-03-21 2020-02-11 Teva Pharmaceuticals International Gmbh Antagonist antibodies directed against calcitonin gene-related peptide and methods using same
WO2021205216A1 (fr) 2020-04-06 2021-10-14 H. Lundbeck A/S Traitement de la plupart des symptômes gênants (mbs) associés à la migraine à l'aide d'anticorps anti-cgrp
WO2023026245A1 (fr) 2021-08-27 2023-03-02 H. Lundbeck A/S Traitement de la céphalée vasculaire de horton à l'aide d'anticorps anti-cgrp

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11951139B2 (en) 2015-11-30 2024-04-09 Seed Health, Inc. Method and system for reducing the likelihood of osteoporosis
US11951140B2 (en) 2011-02-04 2024-04-09 Seed Health, Inc. Modulation of an individual's gut microbiome to address osteoporosis and bone disease
US11844720B2 (en) 2011-02-04 2023-12-19 Seed Health, Inc. Method and system to reduce the likelihood of dental caries and halitosis
CN108373502B (zh) 2011-05-20 2022-03-22 H.伦德贝克公司 抗cgrp组合物及其用途
CN103957935B (zh) * 2011-05-20 2018-04-03 奥尔德生物控股有限责任公司 抗cgrp或抗cgrp‑r抗体或抗体片段用于治疗或预防慢性和急性形式的腹泻的用途
KR102098546B1 (ko) 2011-05-20 2020-04-07 앨더바이오 홀딩스 엘엘씨 필요한 대상체, 특히 편두통 환자의 광선공포증 또는 광선 혐오증을 예방 또는 억제하기 위한 항-cgrp 항체 및 항체 단편의 용도
CA2925546C (fr) 2012-10-29 2022-06-14 The University Of North Carolina At Chapel Hill Methodes et compositions pour traiter des troubles du tissu mucosal
US11826388B2 (en) 2013-12-20 2023-11-28 Seed Health, Inc. Topical application of Lactobacillus crispatus to ameliorate barrier damage and inflammation
US11833177B2 (en) 2013-12-20 2023-12-05 Seed Health, Inc. Probiotic to enhance an individual's skin microbiome
US11839632B2 (en) 2013-12-20 2023-12-12 Seed Health, Inc. Topical application of CRISPR-modified bacteria to treat acne vulgaris
JOP20200116A1 (ar) * 2015-04-24 2017-06-16 Amgen Inc طرق لعلاج أو الوقاية من الصداع النصفي
AU2015413277A1 (en) * 2015-10-30 2018-04-12 Eli Lilly And Company Anti-CGRP/anti-IL-23 bispecific antibodies and uses thereof
US10202435B2 (en) 2016-04-15 2019-02-12 Alder Biopharmaceuticals, Inc. Anti-PACAP antibodies and uses thereof
US11639380B2 (en) 2019-01-08 2023-05-02 H. Lundbeck A/S Acute treatment and rapid treatment of headache using anti-CGRP antibodies
JP7082379B2 (ja) * 2019-03-29 2022-06-08 株式会社サンヨー・シーワィピー 調整画像データ生成装置、色差調整画像表示システム、色差調整画像データ生成方法、色差調整画像データ生成プログラムおよび色差調整画像表示方法

Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
EP0322094A1 (fr) 1987-10-30 1989-06-28 Delta Biotechnology Limited Fragments N-terminaux de la sérum albumine humaine
EP0401384A1 (fr) 1988-12-22 1990-12-12 Kirin-Amgen, Inc. Facteur de stimulation de colonies de granulocytes modifies chimiquement
EP0413622A1 (fr) 1989-08-03 1991-02-20 Rhone-Poulenc Sante Dérivés de l'albumine à fonction thérapeutique
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5624659A (en) 1993-03-19 1997-04-29 Duke University Method of treating brain tumors expressing tenascin
US5627052A (en) 1990-08-02 1997-05-06 B.R. Centre, Ltd. Methods for the production of proteins with a desired function
US5643575A (en) 1993-10-27 1997-07-01 Enzon, Inc. Non-antigenic branched polymer conjugates
US5766883A (en) 1989-04-29 1998-06-16 Delta Biotechnology Limited Polypeptides
US5876969A (en) 1992-01-31 1999-03-02 Fleer; Reinhard Fusion polypeptides comprising human serum albumin, nucleic acids encoding same, and recombinant expression thereof
US6054297A (en) 1991-06-14 2000-04-25 Genentech, Inc. Humanized antibodies and methods for making them
US6187287B1 (en) 1994-08-12 2001-02-13 Immunomedics, Inc. Immunoconjugates and humanized antibodies specific for B-cell lymphoma and leukemia cells
US6407213B1 (en) 1991-06-14 2002-06-18 Genentech, Inc. Method for making humanized antibodies
US6548640B1 (en) 1986-03-27 2003-04-15 Btg International Limited Altered antibodies
US6632927B2 (en) 1989-12-21 2003-10-14 Celltech Therapeutics Limited Humanized antibodies
US20060270045A1 (en) 2003-10-22 2006-11-30 Keck Graduate Institute Methods of synthesizing heteromultimeric polypeptides in yeast using a haploid mating strategy
US20070269868A1 (en) 2006-05-19 2007-11-22 Carvalho Jensen Anne E Culture method for obtaining a clonal population of antigen-specific B cells
WO2008144757A1 (fr) 2007-05-21 2008-11-27 Alder Biopharmaceuticals, Inc. Nouveaux procédés d'humanisation d'anticorps de lapin et anticorps de lapin humanisés
US20090022659A1 (en) 2007-05-21 2009-01-22 Katie Olson Antibodies to TNF alpha and use thereof
US7935340B2 (en) 2007-05-21 2011-05-03 Alderbio Holdings Llc Antibodies to IL-6 and use thereof

Family Cites Families (74)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3662333A (en) 1970-09-08 1972-05-09 Bendix Corp Hydraulic accumulator charge detector and indicating system
US5374618A (en) 1983-06-15 1994-12-20 Celltech Limited Calcitonin peptides, and gene related pharmaceutical compositions
JPS62129297A (ja) 1985-08-09 1987-06-11 Toyo Jozo Co Ltd カルシトニン遺伝子関連ペプチド誘導体
EP0307434B2 (fr) 1987-03-18 1998-07-29 Scotgen Biopharmaceuticals, Inc. Anticorps alteres
US5364841A (en) 1988-01-11 1994-11-15 Amylin Pharmaceuticals, Inc. Treatment of obesity and essential hypertension and related disorders
US5266561A (en) 1988-01-11 1993-11-30 Amylin Pharmaceuticals, Inc. Treatment of type 2 diabetes mellitus
US5116964A (en) 1989-02-23 1992-05-26 Genentech, Inc. Hybrid immunoglobulins
AU7953194A (en) 1994-08-16 1996-03-07 Human Genome Sciences, Inc. Calcitonin receptor
FR2732221B1 (fr) 1995-03-28 1997-04-25 Oreal Utilisation d'un antagoniste de cgrp pour traiter les rougeurs cutanees d'origine neurogene et composition obtenue
JPH11512396A (ja) 1995-09-05 1999-10-26 スミスクライン・ビーチャム・コーポレイション 化合物および方法
EP0934068A1 (fr) 1996-09-09 1999-08-11 Smithkline Beecham Corporation Composes et methodes
BR9712023A (pt) 1996-09-10 1999-08-31 Thomae Gmbh Dr K Aminoácidos derivados, medicamentos contendo esses compostos e processos para a sua preparação.
WO1998056779A1 (fr) 1997-06-13 1998-12-17 Smithkline Beecham Corporation 4-sulfinyle benzamides utiles comme antagonistes du recepteur de peptides lies au gene de la calcitonine
US6956107B2 (en) 1998-02-20 2005-10-18 Tanox, Inc. Inhibitors of complement activation
WO2000018764A1 (fr) 1998-09-30 2000-04-06 Merck Sharp & Dohme Limited Piperidines de benzimidazolinyle en tant que ligands de cgrp
US20010036647A1 (en) 1998-10-22 2001-11-01 Prabhakara V. Choudary Functionally assembled antigen-specific intact recombinant antibody and a method for production thereof
US6737056B1 (en) 1999-01-15 2004-05-18 Genentech, Inc. Polypeptide variants with altered effector function
EP1031350A1 (fr) 1999-02-23 2000-08-30 Warner-Lambert Company Utilisation d'un analogue de la gabapentine pour la fabrication d'un médicament pour la prevention et le traitement des douleurs viscérales
US6313097B1 (en) 1999-03-02 2001-11-06 Boehringer Ingelheim Pharma Kg Antagonists of calcitonin gene-related peptide
US6521609B1 (en) 1999-08-10 2003-02-18 Boehringer Ingelheim Pharma Kg Use of CGRP antagonists and CGRP release inhibitors for combating menopausal hot flushes
AP1775A (en) 1999-09-25 2007-08-28 Univ Iowa Res Found Immunostimulatory nucleic acids.
ES2390761T3 (es) 2000-03-01 2012-11-16 Medimmune, Llc Anticuerpos recombinantes de alta potencia y método para producción de los mismos
US6406863B1 (en) 2000-06-23 2002-06-18 Genetastix Corporation High throughput generation and screening of fully human antibody repertoire in yeast
US20020162125A1 (en) 2001-03-06 2002-10-31 Anne-Marie Salmon Methods and compositions for the modulation of neurogenic inflammatory pain and physical opiate withdrawal
US20030181462A1 (en) 2001-08-17 2003-09-25 Boehringer Ingelheim Pharma Kg Use of BIBN4096 in combination with other antimigraine drugs for the treatment of migraine
CA2471833A1 (fr) 2001-11-26 2003-06-05 Protemix Corporation Limited Procedes et compositions pour normaliser les niveaux lipidiques dans les tissus mammaliens
ES2327830T3 (es) 2002-03-29 2009-11-04 Schering Corporation Anticuerpos monoclonales humanos anti-interleuquina-5 y metodos y composiciones que los contienen.
EP1501929B1 (fr) 2002-05-06 2013-03-27 Noxxon Pharma AG Acides nucleiques liant le cgrp
US20040110170A1 (en) 2002-05-18 2004-06-10 The Regents Of The University Of California Cloning and characterization of calcitonin gene related peptide receptors
US7345065B2 (en) 2002-05-21 2008-03-18 Allergan, Inc. Methods and compositions for alleviating pain
JP4490809B2 (ja) 2002-06-05 2010-06-30 ブリストル−マイヤーズ スクイブ カンパニー カルシトニン遺伝子関連ペプチド受容体拮抗薬
PT1517921E (pt) 2002-06-28 2006-09-29 Domantis Ltd Ligandos duplamente especificos com semi-vida no soro aumentada
BR0313388A (pt) 2002-08-12 2005-07-05 Birkir Sveinsson Método para tratar, remediar ou evitar a psorìase em um paciente, uso de um composto de antagonista de cgrp, composição farmacêutica para tratamento da psorìase, e, método para identificar um composto candidato para o uso em um medicamento para tratar a psorìase
UA80447C2 (en) 2002-10-08 2007-09-25 Methods for treating pain by administering nerve growth factor antagonist and opioid analgesic
DE10250082A1 (de) * 2002-10-25 2004-05-13 Boehringer Ingelheim Pharma Gmbh & Co. Kg Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel
AU2003298816C1 (en) 2002-12-02 2010-12-16 Amgen Fremont, Inc. Antibodies directed to Tumor Necrosis Factor and uses thereof
PT1575517E (pt) 2002-12-24 2012-05-28 Rinat Neuroscience Corp Anticorpos anti-ngf e métodos de utilização dos mesmos
JP4673296B2 (ja) 2003-03-14 2011-04-20 メルク・シャープ・エンド・ドーム・コーポレイション アリールスピロヒダントインｃｇｒｐ受容体拮抗物質
JP4690313B2 (ja) 2003-03-14 2011-06-01 メルク・シャープ・エンド・ドーム・コーポレイション カルボキサミドスピロヒダントインｃｇｒｐ受容体アンタゴニスト
EP1608627B1 (fr) 2003-03-14 2008-05-07 Merck & Co. Inc. Antagonistes des recepteurs du cgrp spirohydantoine anilides bicycliques
JP4673295B2 (ja) 2003-03-14 2011-04-20 メルク・シャープ・エンド・ドーム・コーポレイション 単環式アニリドスピロヒダントインｃｇｒｐ受容体拮抗物質
WO2004087649A2 (fr) 2003-03-14 2004-10-14 Merck & Co., Inc. Antagonistes benodiazepine spirohydantoin des recepteurs de cgrp
WO2004091514A2 (fr) 2003-04-15 2004-10-28 Merck & Co., Inc. Antagonistes des recepteurs de cgrp
JO2355B1 (en) 2003-04-15 2006-12-12 ميرك شارب اند دوم كوربوريشن Hereditary calcitonin polypeptide receptor antagonists
WO2004097421A2 (fr) 2003-04-29 2004-11-11 Bayer Healthcare Ag Diagnostics et traitements destines a des maladies associees au recepteur de type recepteur calcitonine (calcrl)
EP1646611A1 (fr) 2003-07-15 2006-04-19 Merck & Co., Inc. Antagonistes des recepteurs cgrp de l'hydroxypyridine
US20080070239A1 (en) 2003-10-29 2008-03-20 University Of Rochester Detection of neureopeptides associated with pelvic pain disorders and uses thereof
JP2007517911A (ja) * 2004-01-13 2007-07-05 バソジェニックス ファーマシューティカルズ， インコーポレイテッド 心臓血管の適応症および腎臓の適応症に対してｃｇｒｐを使用する方法
DE102004015723A1 (de) 2004-03-29 2005-10-20 Boehringer Ingelheim Pharma Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel
US7279471B2 (en) 2004-04-15 2007-10-09 Boehringer Ingelheim International Gmbh Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions
DE102004018794A1 (de) 2004-04-15 2005-10-27 Boehringer Ingelheim Pharma Gmbh & Co. Kg Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel
TWI432196B (zh) 2005-01-18 2014-04-01 Euro Celtique Sa 內臟痛的治療
EP1770091A1 (fr) 2005-09-29 2007-04-04 Boehringer Ingelheim Pharma GmbH & Co. KG Antagonistes CGRP, leur procédé de préparation ansi que leur utilisation comme médicaments
ITRM20050290A1 (it) 2005-06-07 2006-12-08 Lay Line Genomics Spa Uso di molecole in grado di inibire il legame tra ngf e il suo recettore trka come analgesici ad effetto prolungato.
CA2619856A1 (fr) 2005-08-25 2007-03-01 Wex Pharmaceuticals Inc. Utilisation de bloqueurs des canaux sodiques pour traiter les douleurs viscerales, ou les douleurs provoquees par un traitement anticancereux
US8168592B2 (en) 2005-10-21 2012-05-01 Amgen Inc. CGRP peptide antagonists and conjugates
ES2664421T3 (es) 2005-11-14 2018-04-19 Teva Pharmaceuticals International Gmbh Anticuerpo antagonista dirigido contra un péptido relacionado con el gen de la calcitonina
US20070108378A1 (en) 2005-11-14 2007-05-17 Toru Terabayashi High pressure optical cell for a downhole optical fluid analyzer
JP2009515971A (ja) 2005-11-18 2009-04-16 メルク エンド カムパニー インコーポレーテッド スピロヒダントインアリールｃｇｒｐ受容体アンタゴニスト
WO2007076336A1 (fr) 2005-12-22 2007-07-05 Eli Lilly And Company Traitement de la migraine avec des anticorps anti-cgrp
US9074352B2 (en) 2006-03-27 2015-07-07 John R. Ramun Universal control scheme for mobile hydraulic equipment and method for achieving the same
EP2029234A1 (fr) 2006-06-08 2009-03-04 Boehringer Ingelheim International GmbH Traitement de troubles gastro-intestinaux avec des antagonistes cgrp
WO2008011190A1 (fr) 2006-07-21 2008-01-24 Vertex Pharmaceuticals Incorporated Antagonistes des récepteurs cgrp
US8293239B2 (en) 2008-03-04 2012-10-23 Pfizer Limited Methods of treating chronic pain
ES2584907T3 (es) 2008-03-04 2016-09-30 Labrys Biologics Inc. Métodos para tratamiento del dolor inflamatorio
JO3382B1 (ar) 2008-12-23 2019-03-13 Amgen Inc أجسام مضادة ترتبط مع مستقبل cgrp بشري
WO2011024113A1 (fr) 2009-08-28 2011-03-03 Rinat Neuroscience Corporation Procédés de traitement de la douleur viscérale par administration d'anticorps antagonistes dirigés contre le peptide associé au gène de la calcitonine
AR081434A1 (es) 2010-06-10 2012-08-29 Lilly Co Eli Anticuerpo del peptido relacionado con el gen calcitonina (cgrp), composicion farmaceutica que lo comprende, uso de dicho anticuerpo para preparar un medicamento util para tratar dolor de osteoartritis o migranas y fragmento de union a antigeno de dicho anticuerpo
KR102098546B1 (ko) 2011-05-20 2020-04-07 앨더바이오 홀딩스 엘엘씨 필요한 대상체, 특히 편두통 환자의 광선공포증 또는 광선 혐오증을 예방 또는 억제하기 위한 항-cgrp 항체 및 항체 단편의 용도
CN108373502B (zh) 2011-05-20 2022-03-22 H.伦德贝克公司 抗cgrp组合物及其用途
CN103957935B (zh) 2011-05-20 2018-04-03 奥尔德生物控股有限责任公司 抗cgrp或抗cgrp‑r抗体或抗体片段用于治疗或预防慢性和急性形式的腹泻的用途
US20170114122A1 (en) 2015-10-23 2017-04-27 Alderbio Holdings Llc Regulation of glucose metabolism using anti-cgrp antibodies
JOP20210166A1 (ar) 2019-01-08 2023-01-30 H Lundbeck As علاج الصداع الناتج عن فرط استعمال الأدوية باستخدام أجسام مضادة لـcgrp أو أجسام مضادة لـcgrp-r
US11639380B2 (en) 2019-01-08 2023-05-02 H. Lundbeck A/S Acute treatment and rapid treatment of headache using anti-CGRP antibodies

Patent Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
US6548640B1 (en) 1986-03-27 2003-04-15 Btg International Limited Altered antibodies
EP0322094A1 (fr) 1987-10-30 1989-06-28 Delta Biotechnology Limited Fragments N-terminaux de la sérum albumine humaine
EP0401384A1 (fr) 1988-12-22 1990-12-12 Kirin-Amgen, Inc. Facteur de stimulation de colonies de granulocytes modifies chimiquement
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5585089A (en) 1988-12-28 1996-12-17 Protein Design Labs, Inc. Humanized immunoglobulins
US6180370B1 (en) 1988-12-28 2001-01-30 Protein Design Labs, Inc. Humanized immunoglobulins and methods of making the same
US5693762A (en) 1988-12-28 1997-12-02 Protein Design Labs, Inc. Humanized immunoglobulins
US5766883A (en) 1989-04-29 1998-06-16 Delta Biotechnology Limited Polypeptides
EP0413622A1 (fr) 1989-08-03 1991-02-20 Rhone-Poulenc Sante Dérivés de l'albumine à fonction thérapeutique
US6632927B2 (en) 1989-12-21 2003-10-14 Celltech Therapeutics Limited Humanized antibodies
US5627052A (en) 1990-08-02 1997-05-06 B.R. Centre, Ltd. Methods for the production of proteins with a desired function
US6639055B1 (en) 1991-06-14 2003-10-28 Genentech, Inc. Method for making humanized antibodies
US6054297A (en) 1991-06-14 2000-04-25 Genentech, Inc. Humanized antibodies and methods for making them
US6407213B1 (en) 1991-06-14 2002-06-18 Genentech, Inc. Method for making humanized antibodies
US5876969A (en) 1992-01-31 1999-03-02 Fleer; Reinhard Fusion polypeptides comprising human serum albumin, nucleic acids encoding same, and recombinant expression thereof
US5624659A (en) 1993-03-19 1997-04-29 Duke University Method of treating brain tumors expressing tenascin
US5643575A (en) 1993-10-27 1997-07-01 Enzon, Inc. Non-antigenic branched polymer conjugates
US6187287B1 (en) 1994-08-12 2001-02-13 Immunomedics, Inc. Immunoconjugates and humanized antibodies specific for B-cell lymphoma and leukemia cells
US20060270045A1 (en) 2003-10-22 2006-11-30 Keck Graduate Institute Methods of synthesizing heteromultimeric polypeptides in yeast using a haploid mating strategy
US20070269868A1 (en) 2006-05-19 2007-11-22 Carvalho Jensen Anne E Culture method for obtaining a clonal population of antigen-specific B cells
WO2008144757A1 (fr) 2007-05-21 2008-11-27 Alder Biopharmaceuticals, Inc. Nouveaux procédés d'humanisation d'anticorps de lapin et anticorps de lapin humanisés
US20090022659A1 (en) 2007-05-21 2009-01-22 Katie Olson Antibodies to TNF alpha and use thereof
US7935340B2 (en) 2007-05-21 2011-05-03 Alderbio Holdings Llc Antibodies to IL-6 and use thereof

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
ADAIR; JONES, P.T. ET AL., NATURE, vol. 321, 1986, pages 522 - 525
BOULIANNE, G.L ET AL., NATURE, vol. 312, 1984, pages 643 - 46
CALICETI ET AL., BIOCONJUG. CHEM., vol. 10, 1999, pages 638 - 646
ELSHOURBAGY ET AL., ENDOCRINOLOGY, vol. 139, 1998, pages 1678
GRENNARO, A.,: "Remington's Pharmaceutical Sciences 19th Ed.,", 1995
MALIK ET AL., EXP. HEMATOL., vol. 20, 1992, pages 1028 - 1035
MORPURGO ET AL., APPL. BIOCHEM. BIOTECHNOL., vol. 56, 1996, pages 59 - 72
MORRISON ET AL., P.N.A.S. USA, vol. 81, 1984, pages 8651 - 55
NEUBERGER, M.S., NATURE, vol. 314, 1985, pages 268 - 270
REICHMANN, L. ET AL., NATURE, vol. 332, 1988, pages 323 - 327
SARAGOBI ET AL., SCIENCE, vol. 253, 1991, pages 792 - 795
See also references of EP2709662A4
VERHOEYEN, M ET AL., SCIENCE, vol. 239, 1988, pages 1534 - 36
VOROBJEV ET AL., NUCLEOSIDES NUCLEOTIDES, vol. 18, 1999, pages 2745 - 2750
ZIMMERMAN ET AL., PEPTIDES, vol. 16, 1995, pages 421

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016528198A (ja) * 2013-07-03 2016-09-15 アルダー・バイオファーマシューティカルズ・インコーポレーテッド 抗ｃｇｒｐ抗体を使用したグルコース代謝の調整
JP2018168186A (ja) * 2013-07-03 2018-11-01 アルダー・バイオファーマシューティカルズ・インコーポレーテッド 抗ｃｇｒｐ抗体を使用したグルコース代謝の調整
JP2020158525A (ja) * 2013-07-03 2020-10-01 アルダー・バイオファーマシューティカルズ・インコーポレーテッド 抗ｃｇｒｐ抗体を使用したグルコース代謝の調整
US9896502B2 (en) 2014-03-21 2018-02-20 Teva Pharmaceuticals International Gmbh Antagonist antibodies directed against calcitonin gene-related peptide and methods using same
US10519224B2 (en) 2014-03-21 2019-12-31 Teva Pharmaceuticals International Gmbh Treating headache comprising administering an antibody to calcitonin gene-related peptide
US10556945B2 (en) 2014-03-21 2020-02-11 Teva Pharmaceuticals International Gmbh Antagonist antibodies directed against calcitonin gene-related peptide and methods using same
US11555064B2 (en) 2014-03-21 2023-01-17 Teva Pharmaceuticals International Gmbh Treating headache comprising administering an antibody to calcitonin gene-related peptide
US10392434B2 (en) 2016-09-23 2019-08-27 Teva Pharmaceuticals International Gmbh Treating refractory migraine
US11028160B2 (en) 2016-09-23 2021-06-08 Teva Pharmaceuticals International Gmbh Treating refractory migraine
US11028161B2 (en) 2016-09-23 2021-06-08 Teva Pharmaceuticals International Gmbh Treating refractory migraine
WO2021205216A1 (fr) 2020-04-06 2021-10-14 H. Lundbeck A/S Traitement de la plupart des symptômes gênants (mbs) associés à la migraine à l'aide d'anticorps anti-cgrp
WO2023026245A1 (fr) 2021-08-27 2023-03-02 H. Lundbeck A/S Traitement de la céphalée vasculaire de horton à l'aide d'anticorps anti-cgrp

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